197 results on '"Jon A. Erickson"'
Search Results
2. Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
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Michael J. Lukey, Ahmad A. Cluntun, William P. Katt, Miao-chong J. Lin, Joseph E. Druso, Sekar Ramachandran, Jon W. Erickson, Henry H. Le, Zhihan-Emily Wang, Bryant Blank, Kai Su Greene, and Richard A. Cerione
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Biology (General) ,QH301-705.5 - Abstract
Summary: Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer. : Lukey et al. report that basal- and luminal-subtype breast cancers employ different strategies for glutamine catabolism, impacting their sensitivity profiles to glutaminase inhibitors. Elevated GLS2 expression in luminal-subtype cancers is driven in part by GATA3. Targeting GLS2 with the pan-glutaminase inhibitor 968 inhibits luminal-subtype breast cancer cell proliferation and tumorigenesis. Keywords: breast cancer, glutaminase, glutamine metabolism GLS2, GLS, BPTES, CB-839, 968
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- 2019
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3. Supplementary Figure 2 from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
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PDF file, 48KB, Graph showing 968 potency at multiple doses when 968 is added to GAC before or after inorganic phosphate.
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- 2023
4. Supplementary Figure 3 from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
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PDF file, 50KB, Time dependence of two compounds, 35 and 40, showing that their activity decreases when incubated with GAC for 10 or 20 minutes prior to beginning the enzymatic reaction in the assay.
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- 2023
5. Supplementary Table 1 from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
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PDF file, 294KB, Complete list of compounds examined in the recombinant GAC assay, and % inhibition determined against the enzyme for each compound.
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- 2023
6. Supplementary Methods and Figure Legends from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
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DOC file, 32.5KB.
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- 2023
7. Data from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
- Abstract
One hallmark of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and its inhibition could significantly impact malignant transformation. The small molecule 968, a dibenzophenanthridine, was recently shown to inhibit recombinantly expressed glutaminase C, to block the proliferation and anchorage-independent colony formation of human cancer cells in culture, and to inhibit tumor formation in mouse xenograft models. Here, we examine the structure–activity relationship that leads to 968-based inhibition of glutaminase and cancer cell proliferation, focusing upon a “hot-spot” ring previously identified as critical to 968 activity. We find that the hot-spot ring must be substituted with a large, nonplanar functionality (e.g., a t-butyl group) to bestow activity to the series, leading us to a model whereby the molecule binds glutaminase at a previously undescribed allosteric site. We conduct docking studies to locate potential 968-binding sites and proceed to test a specific set of docking solutions via site-directed mutagenesis. We verify the results from our initial assay of 968 and its analogues by cellular studies using MDA-MB-231 breast cancer cells. Mol Cancer Ther; 11(6); 1269–78. ©2012 AACR.
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- 2023
8. Supplementary Figure 1 from Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
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Richard A. Cerione, Jon W. Erickson, Sekar Ramachandran, and William P. Katt
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PDF file, 118KB, Graph showing dependence of 968 activity upon order in which GAC is exposed to assay reagents.
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- 2023
9. Energy pathways
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Jon D. Erickson
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- 2023
10. Ecozoic
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Jon D. Erickson
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- 2023
11. The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy
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Michael J. Lukey, Kai Su Greene, Jon W. Erickson, Kristin F. Wilson, and Richard A. Cerione
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Science - Abstract
Cancer cells have previously been shown to be addicted to glutamine and glutaminase enzyme activity. Here, the authors show that overexpression of the JUN proto-oncogene in breast cancer cells regulates glutaminaseexpression and is sufficient to confer sensitivity to glutaminase-targeted therapy.
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- 2016
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12. Carbon Dioxide Effects on Plants
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David W. Wolfe and Jon D. Erickson
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- 2022
13. Predicting the Accuracy of Ligand Overlay Methods with Random Forest Models.
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Ravi Nandigam, David A. Evans 0002, Jon A. Erickson, Sangtae Kim, and Jeffrey J. Sutherland
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- 2008
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14. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis
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Joseph E. Druso, B. Blank, Miao-chong J. Lin, Clint A. Stalnecker, Michael J. Lukey, Robert S. Weiss, Kai Su Greene, Xueying Wang, Richard A. Cerione, Chengliang Zhang, Kristin F. Wilson, Yashira L Negrón Abril, Hening Lin, and Jon W. Erickson
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SIRT5 ,Multidisciplinary ,biology ,Glutaminase ,Chemistry ,Cancer ,Biological Sciences ,medicine.disease_cause ,medicine.disease ,Glutamine ,Cancer cell ,Sirtuin ,medicine ,biology.protein ,Cancer research ,NAD+ kinase ,Carcinogenesis - Abstract
Significance The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated in cancer cells, and a GLS-selective inhibitor is being evaluated in clinical trials. Previous screens identified succinylated lysine residues on GLS, but the functional consequences of these posttranslational modifications have remained unclear. Here, we report that the mitochondrial desuccinylase SIRT5 stabilizes GLS. Both GLS and SIRT5 are upregulated during cellular transformation, and high expression of SIRT5 in human breast tumors correlates with poor patient prognosis. Mechanistically, SIRT5-mediated desuccinylation of residue K164 protects GLS from ubiquitination at K158 and from subsequent degradation. These findings reveal an important role for SIRT5 in mammary tumorigenesis and establish a posttranslational mechanism regulating GLS levels. Collectively, they support further investigation of SIRT5 as a potential therapeutic target.
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- 2019
15. A critically modern ecological economics for the Anthropocene
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Michael B. Wironen and Jon D. Erickson
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Global and Planetary Change ,Ecological economics ,010504 meteorology & atmospheric sciences ,Ecology ,Modernity ,media_common.quotation_subject ,Subject (philosophy) ,Geology ,Environmental ethics ,010501 environmental sciences ,01 natural sciences ,Earth system science ,Deliberative democracy ,13. Climate action ,Social system ,Anthropocene ,Sociology ,0105 earth and related environmental sciences ,media_common ,Social theory - Abstract
Ecological economics recognizes economic activity as a biophysical process mediated by social systems and ultimately subject to the constraints of a finite earth system. The Anthropocene discourse appears as validation of the central concerns of ecological economics yet throws into relief its limits as a normative transdiscipline oriented toward social transformation. We review ecological economics in light of two overarching challenges: first, negotiating between biophysical reality and plural constructed social realities, so as to create legitimate grounds for a sustainability transition; second, accounting for multi-level, multi-scale social and political action, which demands a means for arbitrating among competing normative propositions. We argue that attempts to address these challenges within ecological economics have been inconsistent and relatively scarce, reflecting an unresolved tension regarding modern and postmodern social theory. We demonstrate that a critically modern ecological economics could draw on aligned social movements and build on deliberative theory as a foundation for social and political change fit for navigating the Anthropocene.
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- 2019
16. Lessons in Molecular Recognition, 2. Assessing and Improving Cross-Docking Accuracy.
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Jeffrey J. Sutherland, Ravi Nandigam, Jon A. Erickson, and Michal Vieth
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- 2007
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17. KRAS-Dependent Cancer Cells Promote Survival by Producing Exosomes Enriched in Survivin
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Kirsten L. Bryant, Wen Hsuan Chang, Thuy Tien Thi Nguyen, Channing J. Der, Jon W. Erickson, Richard A. Cerione, Marc A. Antonyak, Chia Hsin Hsu, Haoqiang Ying, and Hong Jin Kim
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0301 basic medicine ,Cancer Research ,endocrine system diseases ,Paclitaxel ,Cell Survival ,Survivin ,Cell Communication ,medicine.disease_cause ,Exosomes ,Exosome ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,Pancreatic cancer ,Cell Line, Tumor ,Medicine ,Humans ,neoplasms ,Pancreas ,business.industry ,Imidazoles ,Cancer ,Chloroquine ,Extracellular vesicle ,Fibroblasts ,medicine.disease ,digestive system diseases ,Microvesicles ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Mutation ,Cancer research ,KRAS ,business ,Naphthoquinones - Abstract
Mutations in KRAS frequently occur in human cancer and are especially prevalent in pancreatic ductal adenocarcinoma (PDAC), where they have been shown to promote aggressive phenotypes. However, targeting this onco-protein has proven to be challenging, highlighting the need to further identify the various mechanisms used by KRAS to drive cancer progression. Here, we considered the role played by exosomes, a specific class of extracellular vesicles (EVs) derived from the endocytic cellular trafficking machinery, in mediating the ability of KRAS to promote cell survival. We found that exosomes isolated from the serum of PDAC patients, as well as from KRAS-transformed fibroblasts and pancreatic cancer cells, were all highly enriched in the cell survival protein Survivin. Exosomes containing Survivin, upon engaging serum-starved cells, strongly enhanced their survival. Moreover, they significantly compromised the effectiveness of the conventional chemotherapy drug paclitaxel, as well as a novel therapy that combines an ERK inhibitor with chloroquine, which is currently in clinical trials for PDAC. The survival benefits provided by oncogenic KRAS-derived exosomes were markedly reduced when depleted of Survivin using siRNA or upon treatment with the Survivin inhibitor YM155. Taken together, these findings demonstrate how KRAS mutations give rise to exosomes that provide a unique form of intercellular communication to promote cancer cell survival and therapy resistance, as well as raise interesting possibilities regarding their potential for serving as therapeutic targets and diagnostic markers for KRAS-dependent cancers.
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- 2021
18. Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor
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Stephanie L. Stout, Leonard L. Winneroski, Jorg Hendle, Warren J. Porter, Patrick J. C. May, Leonard N. Boggs, Thomas K. Baker, James P. Beck, Steven James Green, Anthony R. Borders, Erik James Hembre, Stephen L. Lowe, Christopher D Aluise, David L. McKinzie, Brian Morgan Watson, Brian Michael Mathes, Jon A. Erickson, Zhixiang Yang, Patrick J Cocke, Dustin J. Mergott, Brian A. Willis, Scott A. Monk, Pablo Garcia-Losada, David E. Timm, Richard A. Brier, and Jose Eduardo Lopez
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Male ,Drug target ,Elevated liver enzymes ,Crystallography, X-Ray ,01 natural sciences ,Heterocyclic Compounds, 2-Ring ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Dogs ,Drug Stability ,Drug Discovery ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Pyrroles ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,Low dose ,Madin Darby canine kidney cell ,Brain ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,Retinal toxicity ,Liver metabolism ,chemistry ,Blood-Brain Barrier ,Pyrazines ,Cancer research ,Microsomes, Liver ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Penetrant (biochemical) ,Protein Binding - Abstract
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
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- 2021
19. Homology model directed alignment selection for comparative molecular field analysis: Application to photosystem II inhibitors.
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Mehran Jalaie and Jon A. Erickson
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- 2000
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20. Idea2Data: Toward a New Paradigm for Drug Discovery
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Christos A. Nicolaou, Christine Humblet, Hong Hu, Eva M. Martin, Frank C. Dorsey, Thomas M. Castle, Keith Ian Burton, Haitao Hu, Jorg Hendle, Michael J. Hickey, Joel Duerksen, Jibo Wang, and Jon A. Erickson
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Virtual screening ,Process (engineering) ,Computer science ,Drug discovery ,Organic Chemistry ,Drug Discovery ,Computational biology ,Biochemistry ,Throughput (business) ,Transferase inhibitor - Abstract
[Image: see text] Increasing the success rate and throughput of drug discovery will require efficiency improvements throughout the process that is currently used in the pharmaceutical community, including the crucial step of identifying hit compounds to act as drivers for subsequent optimization. Hit identification can be carried out through large compound collection screening and often involves the generation and testing of many hypotheses based on available knowledge. In practice, hypothesis generation can involve the selection of promising chemical structures from compound collections using predictive models built from previous screening/assay results. Available physical collections, typically used during hit identification, are of the order of 10(6) compounds but represent only a small fraction of the small molecule drug-like chemical space. In an effort to survey a larger portion of chemical space and eliminate inefficiencies during hit identification, we introduce a new process, termed Idea2Data (I2D) that tightly integrates computational and experimental components of the drug discovery process. I2D provides the ability to connect a vast virtual collection of compounds readily synthesizable on automated synthesis systems with computational predictive models for the identification of promising structures. This new paradigm enables researchers to process billions of virtual molecules and select structures that can be prepared on automated systems and made available for biological testing, allowing for timely hypothesis testing and follow-up. Since its introduction, I2D has positively impacted several portfolio efforts through identification of new chemical scaffolds and functionalization of existing scaffolds. In this Innovations paper, we describe the I2D process and present an application for the discovery of new ULK inhibitors.
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- 2019
21. Gain-of-function screen of α-transducin identifies an essential phenylalanine residue necessary for full effector activation
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Chenyue Wang, Jon W. Erickson, Richard A. Cerione, Shawn K. Milano, and Sekar Ramachandran
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0301 basic medicine ,Rhodopsin ,Gs alpha subunit ,Protein Conformation ,G protein ,Phenylalanine ,Recombinant Fusion Proteins ,Protein subunit ,GTP-Binding Protein alpha Subunits, Gi-Go ,Biochemistry ,03 medical and health sciences ,Heterotrimeric G protein ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Animals ,Humans ,Transducin ,Binding site ,Molecular Biology ,Cyclic Nucleotide Phosphodiesterases, Type 6 ,biology ,Effector ,Chemistry ,Cell Biology ,Cell biology ,Enzyme Activation ,HEK293 Cells ,030104 developmental biology ,Gain of Function Mutation ,biology.protein ,Cattle ,Signal Transduction ,Adenylyl Cyclases - Abstract
Two regions on the α subunits of heterotrimeric GTP-binding proteins (G-proteins), the Switch II/α2 helix (which changes conformation upon GDP–GTP exchange) and the α3 helix, have been shown to contain the binding sites for their effector proteins. However, how the binding of Gα subunits to their effector proteins is translated into the stimulation of effector activity is still poorly understood. Here, we took advantage of a reconstituted rhodopsin-coupled phototransduction system to address this question and identified a distinct surface and an essential residue on the α subunit of the G-protein transducin (α(T)) that is necessary to fully activate its effector enzyme, the cGMP phosphodiesterase (PDE). We started with a chimeric G-protein α subunit (α(T)*) comprising residues mainly from α(T) and a short stretch of residues from the G(i1) α subunit (α(i1)), which only weakly stimulates PDE activity. We then reinstated the α(T) residues by systematically replacing the corresponding α(i1) residues within α(T)* with the aim of fully restoring PDE stimulatory activity. These experiments revealed that the αG/α4 loop and a phenylalanine residue at position 283 are essential for conferring the α(T)* subunit with full PDE stimulatory capability. We further demonstrated that this same region and amino acid within the α subunit of the G(s) protein (α(s)) are necessary for full adenylyl cyclase activation. These findings highlight the importance of the αG/α4 loop and of an essential phenylalanine residue within this region on Gα subunits α(T) and α(s) as being pivotal for their selective and optimal stimulation of effector activity.
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- 2018
22. An Intelligent Space Robot for Crew Help and Crew and Equipment Retrieval.
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Jon D. Erickson, Keith A. Grimm, Tom W. Pendleton, Laura E. Howard, Robert A. Goode, M. S. Hawkins, Dave Bloss, Jody A. Seaborn, Cliff W. Hess, Doug Walker, Dale E. Phinney, Robert S. Norsworthy, Greg Anderson, Chiun-Hong Chien, Lisa Hewgill, Mark Littlefield, and Frank Gaudiano
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- 1995
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23. Quantum Mechanical Investigation of Three-Dimensional Activity Cliffs Using the Molecules-in-Molecules Fragmentation-Based Method
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Krishnan Raghavachari, Bishnu Thapa, and Jon A. Erickson
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Materials science ,010304 chemical physics ,High interest ,General Chemical Engineering ,Chemistry, Pharmaceutical ,Binding energy ,Solvation ,Proteins ,General Chemistry ,Interaction energy ,Library and Information Sciences ,Ligands ,01 natural sciences ,0104 chemical sciences ,Computer Science Applications ,010404 medicinal & biomolecular chemistry ,Chemical physics ,Drug Design ,0103 physical sciences ,High activity ,Molecule ,Quantum Theory ,Desolvation ,Quantum ,Protein Binding - Abstract
The concept of activity cliff (AC) (i.e., a small structural modification resulting in a substantial bioactivity change) is widely encountered in medicinal chemistry during compound design. Whereas the study of ACs is of high interest as it provides a wealth of opportunities for effective drug design, its practical application in the actual drug development process has been difficult because of significant computational challenges. To provide some understanding of the ACs, we have carried out a rigorous quantum-mechanical investigation of the electronic interactions of a wide range of ACs (205 cliffs formed by 261 protein-ligand complexes covering 37 different receptor types) using multilayer molecules-in-molecules (MIM) fragmentation-based methodology. The MIM methodology enables performing accurate high-level quantum mechanical (QM) calculations at a substantially lower computational cost, while allowing for a quantitative decomposition of the protein-ligand binding energy into the contributions from individual residues, solvation, and entropy. Our investigation in this study is mainly focused on whether the QM binding energy calculation can correctly identify the higher potency cliff partner for a given ligand pair having a sufficiently high activity difference. We have also analyzed the effect of including crystal water molecules as a part of the receptor as well as the impact of ligand desolvation energy on the correct identification of the more potent ligand in a cliff pair. Our analysis reveals that, in the majority of the cases, the AC prediction could be significantly improved by carefully identifying the critical crystal water molecules, whereas the contribution from the ligand desolvation also remains essential. Additionally, we have exploited the residue-specific interaction energies provided by MIM to identify the key residues and interaction hot-spots that are responsible for the experimentally observed drastic activity changes. The results show that our MIM fragmentation-based protocol provides comprehensive interaction energy profiles that can be employed to understand the distinctiveness of ligand modifications, for potential applications in structure-based drug design.
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- 2020
24. Introduction: what is ecological economics and why do we need it now more than ever
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Ida Kubiszewski, Robert Costanza, Joshua Farley, and Jon D. Erickson
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Ecological economics ,Economics ,Environmental ethics - Published
- 2020
25. Money, interest rates and accumulation on a finite planet: revisiting the ‘monetary growth imperative’ through institutionalist approaches
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Charles Guay-Boutet, Romain Svartzman, Joshua Farley, Jon D. Erickson, Joseph Ament, David Barmes, and Nicolas Kosoy
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Institutionalisation ,Generalization (learning) ,media_common.quotation_subject ,Debt ,medicine ,Economics ,Capitalism ,medicine.symptom ,Neoclassical economics ,Social constructionism ,Collapse (medical) ,Interest rate ,media_common - Abstract
Ecological economists have often argued that the very nature of modern money, created by banks through interest-bearing debt, forces our socio-economic system to seek perpetual growth if we are to avoid a systemic collapse. The foundations of this so-called ‘monetary growth imperative’ suffer from theoretical weaknesses, as shown by several scholars who have used post-Keynesian theory and models to support their claims. However, this critique relies on an incomplete assessment of money, missing its institutional dimensions. The way money is created, circulated and destroyed is the result of social constructs, and historical accounts indicate that the progressive generalization of interest-bearing debt money since the thirteenth century marks a distinct development in the institutionalization of capitalism and its multiple growth imperatives. As such, “monetary contestations†aimed at diminishing the importance of interest rates remain critical to achieving a post-growth socio-economic system.
- Published
- 2020
26. Principles of stakeholder engagement for ecological economics
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Madhavi Venkatesan, Christine Carmichael, and Jon D. Erickson
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Ecological economics ,Stakeholder engagement ,Environmental ethics ,Sociology - Published
- 2020
27. Sustainable Wellbeing Futures
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Jon D. Erickson, Joshua Farley, Ida Kubiszewski, and Robert Costanza
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Economic growth ,Economics ,Futures contract - Published
- 2020
28. Re-establishing Justice as a Pillar of Ecological Economics Through Feminist Perspectives
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Patricia E. Perkins, Jon D. Erickson, and Phoebe Spencer
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Economics and Econometrics ,Ecological economics ,010504 meteorology & atmospheric sciences ,media_common.quotation_subject ,Environmental ethics ,Toleration ,Human condition ,010501 environmental sciences ,01 natural sciences ,Individualism ,Feminist theory ,Framing (social sciences) ,Sociology ,Distributive justice ,Discipline ,0105 earth and related environmental sciences ,General Environmental Science ,media_common - Abstract
Ecological economics has long claimed distributive justice as a central tenet, yet discussions of equity and justice have received relatively little attention over the history of the field. While ecological economics has aspired to be transdisciplinary, its framing of justice is hardly pluralistic. Feminist perspectives and justice frameworks offer a structure for appraising the human condition that bridges social and ecological issues. Through a brief overview of the uptake of feminist perspectives in other social sciences, this paper outlines an initial justice-integration strategy for ecological economics by providing both a point of entry for readers to the vast and diverse field of feminist economic thought, as well as a context for the process of disciplinary evolution in social sciences. We also critique ecological economics' toleration of neoclassical mainstays such as individualism that run counter to justice goals. The paper concludes with a call for ecological economics practitioners and theorists to learn from other social sciences and elevate their attention to justice, to open possibilities for more dynamic, interdisciplinary, community-oriented, and pluralistic analysis.
- Published
- 2018
29. Genuine Economic Progress in the United States: A Fifty State Study and Comparative Assessment
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Mairi-Jane V. Fox and Jon D. Erickson
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Economics and Econometrics ,010504 meteorology & atmospheric sciences ,010501 environmental sciences ,01 natural sciences ,0105 earth and related environmental sciences ,General Environmental Science - Published
- 2018
30. A 'one health' approach to address emerging zoonoses: the HALI project in Tanzania.
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Jonna A K Mazet, Deana L Clifford, Peter B Coppolillo, Anil B Deolalikar, Jon D Erickson, and Rudovick R Kazwala
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Medicine - Published
- 2009
- Full Text
- View/download PDF
31. Conformational changes in the activation loop of mitochondrial glutaminase C: A direct fluorescence readout that distinguishes the binding of allosteric inhibitors from activators
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Richard A. Cerione, Jon W. Erickson, and Clint A. Stalnecker
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0301 basic medicine ,Allosteric regulation ,Benzeneacetamides ,Mutation, Missense ,Enzyme Activators ,Sulfides ,Biochemistry ,Protein Structure, Secondary ,Mitochondrial Proteins ,Mice ,03 medical and health sciences ,Enzyme activator ,Allosteric Regulation ,Glutaminase ,Tetramer ,Thiadiazoles ,Animals ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Quenching (fluorescence) ,biology ,Cell Biology ,Spectrometry, Fluorescence ,Metabolism ,030104 developmental biology ,Enzyme ,Amino Acid Substitution ,Allosteric enzyme ,chemistry ,biology.protein ,Biophysics - Abstract
The first step in glutamine catabolism is catalysis by the mitochondrial enzyme glutaminase, with a specific isoform, glutaminase C (GAC), being highly expressed in cancer cells. GAC activation requires the formation of homotetramers, promoted by anionic allosteric activators such as inorganic phosphate. This leads to the proper orientation of a flexible loop proximal to the dimer-dimer interface that is essential for catalysis (i.e. the “activation loop”). A major class of allosteric inhibitors of GAC, with the prototype being bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and the related molecule CB-839, binds to the activation loop and induces the formation of an inactive tetramer (two inhibitors bound per active tetramer). Here we describe a direct readout for monitoring the dynamics of the activation loop of GAC in response to these allosteric inhibitors, as well as allosteric activators, through the substitution of phenylalanine at position 327 with tryptophan (F327W). The tryptophan fluorescence of the GAC(F327W) mutant undergoes a marked quenching upon the binding of BPTES or CB-839, yielding titration profiles that make it possible to measure the binding affinities of these inhibitors for the enzyme. Allosteric activators like phosphate induce the opposite effect (i.e. fluorescence enhancement). These results describe direct readouts for the binding of the BPTES class of allosteric inhibitors as well as for inorganic phosphate and related activators of GAC, which should facilitate screening for additional modulators of this important metabolic enzyme.
- Published
- 2017
32. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity
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Charles H. Mitch, Aiping Zhang, Mercedes Carpintero, Bradley Condon, C. Groshong, Shane Atwell, John W. Koss, Carl D Overshiner, Jeffrey M. Schkeryantz, Stephon C. Smith, Mark G. Bures, James E. Matt, S.R. Wasserman, Adam M. Fivush, Wesley Seidel, Carlos Jaramillo, K. Conners, David W. Bedwell, Jeffrey M. Witkin, Maria-Jesus Blanco, Daniel Ray Mayhugh, Steven James Quimby, Bruce A. Dressman, Keith A. Wafford, John T. Catlow, Allie Edward Tripp, Paul L. Ornstein, Mario Barberis, José Francisco Soriano, Steven Swanson, Beverly A. Heinz, Jon A. Erickson, Xia Li, Iain MacEwan, Thomas C. Britton, James A. Monn, Susana García-Cerrada, Jing Wang, Mark Donald Chappell, Eric George Tromiczak, Renhua Li, José Eugenio de Diego, Christine Sougias, Tatiana Natali Vetman, Xushan Wang, and Stephen Antonysamy
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0301 basic medicine ,chemistry.chemical_classification ,Metabotropic glutamate receptor 5 ,Hydrochloride ,medicine.drug_class ,Stereochemistry ,Antagonist ,Receptor antagonist ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Dicarboxylic acid ,Metabotropic receptor ,chemistry ,APICA ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,030217 neurology & neurosurgery - Abstract
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharm...
- Published
- 2016
33. Reconstitution of the Rhodopsin-Transducin Complex into Lipid Nanodiscs
- Author
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Yang, Gao, Jon W, Erickson, Richard A, Cerione, and Sekar, Ramachandran
- Subjects
Rhodopsin ,Detergents ,Lipid Bilayers ,Animals ,Transducin ,Nanostructures - Abstract
Transmembrane proteins, such as G protein-coupled receptors (GPCR), require solubilization in detergents prior to purification. The recent development of novel detergents has allowed for the stabilization of GPCRs, which typically have a high degree of structural flexibility and are otherwise subject to denaturation. However, the detergent micelle environment is still very different from the native lipid membrane and the activity of GPCRs can be profoundly affected by interactions with annular lipid molecules. Moreover, GPCRs are often palmitoylated at their intracellular side, and a lipid bilayer environment would allow for proper orientation of these lipid modifications. Therefore, a reconstituted lipid bilayer environment would best mimic the physiological receptor microenvironment for biophysical studies of GPCRs and nanodiscs provide a methodology to address this aim. Nanodiscs are lipid bilayer discs stabilized by amphipathic membrane scaffolding proteins (MSP) where detergent-solubilized transmembrane proteins can be incorporated into them through a self-assembly process. Here we present a method for reconstituting the purified detergent-solubilized rhodopsin-transducin complex, the GPCR-G protein complex in visual phototransduction, into nanodiscs. The resulting complex incorporated into lipid nanodiscs can be used in biophysical studies including small-angle X-ray scattering and electron microscopy. This method is applicable to integral membrane proteins that mediate protein lipidation, including the zDHHC-family of S-acyltransferases and membrane-bound O-acyltransferases.
- Published
- 2019
34. Purification of the Rhodopsin-Transducin Complex for Structural Studies
- Author
-
Yang, Gao, Jon W, Erickson, Richard A, Cerione, and Sekar, Ramachandran
- Subjects
Rhodopsin ,Multiprotein Complexes ,Cell Membrane ,Animals ,Cattle ,Transducin ,Protein Structure, Quaternary ,Retina - Abstract
G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and are targets for over 30% of all drugs on the market. Structural information of GPCRs and more importantly that of the complex between GPCRs and their signaling partner heterotrimeric G proteins is of great importance. Here we present a method for the large-scale purification of the rhodopsin-transducin complex, the GPCR-G protein signaling complex in visual phototransduction, directly from their native retinal membrane using native proteins purified from bovine retinae. Formation of the complex on native membrane is orchestrated in part by the proper engagement of lipid-modified rhodopsin and transducin (i.e., palmitoylation of the rhodopsin C-terminus, myristoylation and farnesylation of the α
- Published
- 2019
35. Deliberation and the Promise of a Deeply Democratic Sustainability Transition
- Author
-
Jon D. Erickson, Robert V. Bartlett, and Michael B. Wironen
- Subjects
010504 meteorology & atmospheric sciences ,media_common.quotation_subject ,Geography, Planning and Development ,lcsh:TJ807-830 ,lcsh:Renewable energy sources ,010501 environmental sciences ,Management, Monitoring, Policy and Law ,sustainability transitions ,Development theory ,ecological economics ,01 natural sciences ,Deliberative democracy ,Political science ,Normative science ,lcsh:Environmental sciences ,0105 earth and related environmental sciences ,media_common ,lcsh:GE1-350 ,Ecological economics ,Renewable Energy, Sustainability and the Environment ,lcsh:Environmental effects of industries and plants ,Environmental ethics ,Building and Construction ,Deliberation ,normative science ,lcsh:TD194-195 ,Legitimation ,Sustainability ,Normative ,modernity ,deliberative democracy ,social-ecological transformations - Abstract
Ecological economics arose as a normative transdiscipline aiming to generate knowledge and tools to help transition the economy toward a scale which is sustainable within the bounds of the earth system. Yet it remains unclear in practice how to legitimize its explicitly normative agenda. One potential means for legitimation can be found in deliberative social and political theory. We review how deliberative theory has informed ecological economics, pointing to three uses: first, to support valuation of non-market goods and services; second, to inform environmental decision-making more broadly; third, to ground alternative theories of development and wellbeing. We argue that deliberation has been used as problem-solving theory, but that its more radical implications have rarely been embraced. Embracing a deliberative foundation for ecological economics raises questions about the compatibility of deeply democratic practice and the normative discourses arguing for a sustainability transition. We highlight three potential mechanisms by which deliberation may contribute to a sustainability transition: preference formation; normative evaluation; and legitimation. We explore each in turn, demonstrating the theoretical possibility that deliberation may be conducive in and of itself to a sustainability transition. We point to a series of challenges facing the “scaling up” of deliberative systems that demand further empirical and theoretical work. These challenges constitute a research agenda for a deeply democratic sustainability transition and can inform the future development of ecological economics and other normative, critical transdisciplines.
- Published
- 2019
36. Reconstitution of the Rhodopsin–Transducin Complex into Lipid Nanodiscs
- Author
-
Yang Gao, Richard A. Cerione, Jon W. Erickson, and Sekar Ramachandran
- Subjects
0303 health sciences ,biology ,Chemistry ,030302 biochemistry & molecular biology ,Protein lipidation ,Transmembrane protein ,03 medical and health sciences ,Rhodopsin ,Biophysics ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Denaturation (biochemistry) ,Transducin ,Lipid bilayer ,Integral membrane protein ,030304 developmental biology ,G protein-coupled receptor - Abstract
Transmembrane proteins, such as G protein-coupled receptors (GPCR), require solubilization in detergents prior to purification. The recent development of novel detergents has allowed for the stabilization of GPCRs, which typically have a high degree of structural flexibility and are otherwise subject to denaturation. However, the detergent micelle environment is still very different from the native lipid membrane and the activity of GPCRs can be profoundly affected by interactions with annular lipid molecules. Moreover, GPCRs are often palmitoylated at their intracellular side, and a lipid bilayer environment would allow for proper orientation of these lipid modifications. Therefore, a reconstituted lipid bilayer environment would best mimic the physiological receptor microenvironment for biophysical studies of GPCRs and nanodiscs provide a methodology to address this aim. Nanodiscs are lipid bilayer discs stabilized by amphipathic membrane scaffolding proteins (MSP) where detergent-solubilized transmembrane proteins can be incorporated into them through a self-assembly process. Here we present a method for reconstituting the purified detergent-solubilized rhodopsin-transducin complex, the GPCR-G protein complex in visual phototransduction, into nanodiscs. The resulting complex incorporated into lipid nanodiscs can be used in biophysical studies including small-angle X-ray scattering and electron microscopy. This method is applicable to integral membrane proteins that mediate protein lipidation, including the zDHHC-family of S-acyltransferases and membrane-bound O-acyltransferases.
- Published
- 2019
37. Purification of the Rhodopsin–Transducin Complex for Structural Studies
- Author
-
Jon W. Erickson, Richard A. Cerione, Sekar Ramachandran, and Yang Gao
- Subjects
0301 basic medicine ,genetic structures ,biology ,G protein ,Chemistry ,05 social sciences ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,Palmitoylation ,Rhodopsin ,Heterotrimeric G protein ,0502 economics and business ,biology.protein ,050211 marketing ,sense organs ,Transducin ,Visual phototransduction ,Myristoylation ,G protein-coupled receptor - Abstract
G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and are targets for over 30% of all drugs on the market. Structural information of GPCRs and more importantly that of the complex between GPCRs and their signaling partner heterotrimeric G proteins is of great importance. Here we present a method for the large-scale purification of the rhodopsin-transducin complex, the GPCR-G protein signaling complex in visual phototransduction, directly from their native retinal membrane using native proteins purified from bovine retinae. Formation of the complex on native membrane is orchestrated in part by the proper engagement of lipid-modified rhodopsin and transducin (i.e., palmitoylation of the rhodopsin C-terminus, myristoylation and farnesylation of the αT and γ1, respectively). The resulting complex is of high purity and stability and has proved suitable for further biophysical and structural studies. The methods described here should be applicable to other recombinantly expressed receptors from insect cells or mamalian cells by forming stable, functional complexes directly on purified cell membranes.
- Published
- 2019
38. Rethinking the geography of energy transitions: low carbon energy pathways through energyshed design
- Author
-
Austin Thomas and Jon D. Erickson
- Subjects
Consumption (economics) ,Renewable Energy, Sustainability and the Environment ,business.industry ,Corporate governance ,Energy (esotericism) ,05 social sciences ,0211 other engineering and technologies ,0507 social and economic geography ,Energy Engineering and Power Technology ,chemistry.chemical_element ,Climate change ,02 engineering and technology ,Environmental economics ,Energy pathways ,Supply and demand ,Fuel Technology ,Nuclear Energy and Engineering ,chemistry ,Distributed generation ,021108 energy ,business ,050703 geography ,Carbon ,Social Sciences (miscellaneous) - Abstract
Energy systems are inherently spatial entities, encompassing infrastructure and land requirements; diverse perspectives of energy system stakeholders tied to locations of supply and demand; and ultimately a spatial distribution of profits, environmental impacts, and societal changes. The spatial relationships between these social and physical components of the energy system drive its ongoing evolution in response to technological advancements, economic trends, and policy directives. A low carbon energy system transition undertaken in response to climate change will require rapid and substantial changes to all of these elements and more. To capture these relationships and inform the design of a low carbon future, we propose the use of energyshed planning. An energyshed is the geographic area that contains the land, infrastructure, people, profits, and environmental impacts connected to final energy consumption. Four distinct decarbonization scenarios are explored: each pathway strikes a different balance between centralized or decentralized energy systems and corporatized or democratized energy system governance. Finally, the energyshed lens is used to perform an initial assessment of the barriers and opportunities for U.S. states to implement a near-term low carbon transition.
- Published
- 2021
39. Mechanistic Basis of Glutaminase Activation
- Author
-
Sekar Ramachandran, Qingqiu Huang, Yunxing Li, Jon W. Erickson, Clint A. Stalnecker, Richard A. Cerione, and William P. Katt
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,biology ,Glutaminase ,Allosteric regulation ,Mutagenesis ,Active site ,Cell Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Enzyme ,Protein structure ,chemistry ,Biosynthesis ,030220 oncology & carcinogenesis ,Hydrolase ,biology.protein ,Molecular Biology - Abstract
Glutamine-derived carbon becomes available for anabolic biosynthesis in cancer cells via the hydrolysis of glutamine to glutamate, as catalyzed by GAC, a splice variant of kidney-type glutaminase (GLS). Thus, there is significant interest in understanding the regulation of GAC activity, with the suggestion being that higher order oligomerization is required for its activation. We used x-ray crystallography, together with site-directed mutagenesis, to determine the minimal enzymatic unit capable of robust catalytic activity. Mutagenesis of the helical interface between the two pairs of dimers comprising a GAC tetramer yielded a non-active, GAC dimer whose x-ray structure displays a stationary loop (“activation loop”) essential for coupling the binding of allosteric activators like inorganic phosphate to catalytic activity. Further mutagenesis that removed constraints on the activation loop yielded a constitutively active dimer, providing clues regarding how the activation loop communicates with the active site, as well as with a peptide segment that serves as a “lid” to close off the active site following substrate binding. Our studies show that the formation of large GAC oligomers is not a pre-requisite for full enzymatic activity. They also offer a mechanism by which the binding of activators like inorganic phosphate enables the activation loop to communicate with the active site to ensure maximal rates of catalysis, and promotes the opening of the lid to achieve optimal product release. Moreover, these findings provide new insights into how other regulatory events might induce GAC activation within cancer cells.
- Published
- 2016
40. Bridging organizations in agricultural carbon markets and poverty alleviation: An analysis of pro-Poor carbon market projects in East Africa
- Author
-
Jean Lee, Jon D. Erickson, Micah Ingalls, and Eva K. Wollenberg
- Subjects
Global and Planetary Change ,Economic growth ,Food security ,010504 meteorology & atmospheric sciences ,Ecology ,Poverty ,Natural resource economics ,media_common.quotation_subject ,Geography, Planning and Development ,010501 environmental sciences ,Management, Monitoring, Policy and Law ,Livelihood ,Payment ,01 natural sciences ,Climate change mitigation ,Economics ,Carbon credit ,Speculation ,Database transaction ,0105 earth and related environmental sciences ,media_common - Abstract
International agricultural carbon market projects face significant challenges in delivering greenhouse gas mitigation objectives whilst also seeking to provide additional benefits for poverty alleviation. The carbon credit producer (the smallholder farmer) and carbon credit buyer in the carbon market transaction typically operate at different spatial and temporal scales. Buyers operate at a global scale, responding to opportunities for financial speculation and both private and public climate action plans. Farmers operate within households, farms, and immediate agricultural landscapes, pursuing livelihood and food security needs. These different scales often result in mismatches of timing, payment, and knowledge in market transactions and can be partially rectified by project developers who serve to broker the relationship between the farmers and the buyers. We examined eight East African agricultural carbon market projects to determine how project developers function as bridging organizations and minimize the mismatches between these actors. Results show that projects better bridged the timing and payment gap between buyers and producers when project developers provided non-monetary benefits or direct monetary assistance to farmers. However, knowledge gaps remained a significant barrier for farmers wishing to participate in the market. We discuss how project developers brokered relationships in ways that reflected their interests and highlight the limitations, trade-offs, and challenges that must be overcome if win-win outcomes of poverty alleviation and climate change mitigation are to be realized.
- Published
- 2016
41. Defeat the Peak: Behavioral insights for electricity demand response program design
- Author
-
Bonnie Wylie Pratt and Jon D. Erickson
- Subjects
Renewable Energy, Sustainability and the Environment ,Energy Engineering and Power Technology ,Environmental economics ,Electric utility ,Demand response ,Fuel Technology ,Incentive ,Nuclear Energy and Engineering ,Malleability ,Work (electrical) ,Return on investment ,Environmental impact assessment ,Business ,Program Design Language ,Social Sciences (miscellaneous) - Abstract
Electric utilities and regulators primarily rely on rate design strategies and economic incentives to achieve customer load malleability at the residential level. However, demand-side management strategies are broadening to incorporate new motivational cues based on pro-social impulses to reduce negative environmental impact and contribute meaningfully to local communities. This evolving relationship between residential customers and utilities is explored to better understand the potential for load malleability achieved through non-economic incentive structures and rate design. Following a review of interdisciplinary perspectives on pro-social behavior and utility demand-side management strategies, we analyze the impact of a pro-social demand response program on the energy use of over 16,000 households served by a municipally owned electric utility in Burlington, Vermont, USA. Results indicate that the program achieved a 13.5% decrease in energy use during the peak annual event in August 2018 with a return on investment of 11 to 1 for the distribution utility. This study builds on the work of other researchers studying individual energy behavior change and supports the argument that pro-social incentives can improve the effectiveness of demand response programs.
- Published
- 2020
42. Design and meaning of the genuine progress indicator: A statistical analysis of the U.S. fifty-state model
- Author
-
Mairi-Jane Fox and Jon D. Erickson
- Subjects
Sustainable development ,Economics and Econometrics ,Genuine progress indicator ,010504 meteorology & atmospheric sciences ,Public economics ,Cost–benefit analysis ,media_common.quotation_subject ,Corporate governance ,010501 environmental sciences ,01 natural sciences ,Gross domestic product ,Scholarship ,Community of practice ,Economics ,Quality (business) ,0105 earth and related environmental sciences ,General Environmental Science ,media_common - Abstract
The Genuine Progress Indicator (GPI) was designed to reveal the trade-offs between costs and benefits of economic growth. Although originally estimated and contrasted with Gross Domestic Product (GDP) at national scales, an interest in a state-level adoption has developed in the United States to inform and guide policy. As GPI scholarship and a community of practice has developed, questions have arisen about the quality and legitimacy of the GPI. To investigate, we apply a composite indicator analysis developed by the Organization for Economic Co-operation and Development (OECD) to fifty US state GPI estimates using a consistent method. We focus on a multi-variate analysis of the structure of the composite, sensitivity to weighting and aggregation assumptions, and the statistical relationship with other well-being indicators. Results are heavily influenced by a small number of components, point to a number of unintended policy outcomes, and have mixed relationships with allied indicators. The study suggests steps towards shared GPI governance among practitioners and researchers, consideration of data parsimony and potential double-counting, and data selection criteria to help fill gaps, prioritize needs, and better articulate the purpose and meaning of GPI.
- Published
- 2020
43. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints
- Author
-
David E. Timm, Leonard N. Boggs, Brian Michael Mathes, Yuan Shi, Mario Barberis, Zhixiang Yang, Dustin J. Mergott, Scott A. Monk, Pablo Garcia-Losada, Jose Miguel Minguez, Leonard L. Winneroski, Jon A. Erickson, Richard A. Brier, Anthony R. Borders, Stephanie L. Stout, Porter Warren J, Zoran Rankovic, Jose Eduardo Lopez, Erik James Hembre, James E. Audia, Jorg Hendle, James P. Beck, Steven James Green, Brian Morgan Watson, Patrick C. May, and Robert D. Boyer
- Subjects
Cyclopropanes ,Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alzheimer Disease ,mental disorders ,Drug Discovery ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Molecular Biology ,Biological evaluation ,Hydrolase inhibitor ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Biological activity ,Ligand (biochemistry) ,Molecular Medicine ,Organic synthesis ,Amyloid Precursor Protein Secretases - Abstract
Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.
- Published
- 2020
44. Modeling, Control, and Stability of Smart Loads Toward Grid of Nanogrids for Smart Cities
- Author
-
Dustin Rogge, Anil Pahwa, Mohsen S. Pilehvar, James McDaniel, Joseph Benzaquen, Mohammad B. Shadmand, Jon C. Erickson, and Behrooz Mirafzal
- Subjects
Electricity generation ,Computer science ,020208 electrical & electronic engineering ,Control (management) ,0202 electrical engineering, electronic engineering, information engineering ,020207 software engineering ,02 engineering and technology ,Grid ,Stability (probability) ,Automotive engineering ,Power (physics) ,Voltage - Abstract
Low inertia power generation units make islanded microgrids and nanogrids more vulnerable to voltage and power fluctuations. Smart loads are a possible solution to suppress voltage and power fluctuations in islanded nanogrids. Since smart loads utilize inverters with short-time responses, their dynamics would have a considerable effect on the dynamics and stability of nanogrids, Therefore, the dynamics of smart loads play a significant role for stability analysis of these systems. This paper analyzes the dynamic behaviors of smart loads in nanogrids. Furthermore, a state-space model is developed for smart loads. The stability of smart loads is studied using the developed model, along with circuit simulations. The case study simulations are provided to verify the performance of utilizing smart loads in mitigating voltage and power fluctuations in islanded nanogrids.
- Published
- 2018
45. Theoretical Study of Protein-Ligand Interactions Using the Molecules-in-Molecules Fragmentation-Based Method
- Author
-
Bishnu Thapa, Krishnan Raghavachari, Jon A. Erickson, and Daniel Beckett
- Subjects
Protein Conformation ,Implicit solvation ,010402 general chemistry ,Ligands ,01 natural sciences ,Molecular Docking Simulation ,Protein structure ,Fragmentation (mass spectrometry) ,0103 physical sciences ,Molecule ,Humans ,Physical and Theoretical Chemistry ,Databases, Protein ,Physics ,Quantitative Biology::Biomolecules ,010304 chemical physics ,Ligand ,Proteins ,Interaction energy ,0104 chemical sciences ,Computer Science Applications ,Chemical physics ,Quantum Theory ,Thermodynamics ,Protein ligand ,Protein Binding - Abstract
We have recently significantly expanded the applicability of our Molecules-in-Molecules (MIM) fragmentation method to large proteins by developing a three-layer model (MIM3) in which an accurate quantum-mechanical method is used in conjunction with a cost-effective, dispersion-corrected semiempirical model to overcome previous computational bottlenecks. In this work, we develop MIM3 as a structure-based drug design tool by application of the methodology for the accurate calculation of protein-ligand interaction energies. A systematic protocol is derived for the determination of the geometries of the protein-ligand complexes and to calculate their accurate interaction energies in the gas phase using MIM3. We also derive a simple and affordable procedure based on implicit solvation models and the ligand solvent-accessible surface area to approximate the ligand desolvation penalty in gas-phase interaction energy calculations. We have carefully assessed how closely such interaction energies, which are based on a single protein-ligand conformation, display correlations with the experimentally determined binding affinities. The performance of MIM3 was evaluated on a total of seven data sets comprising 89 protein-ligand complexes, all with experimentally known binding affinities, using a binding pocket involving a quantum region ranging in size from 250 to 600 atoms. The dispersion-corrected B97-D3BJ density functional, previously known to perform accurately for calculations involving non-covalent interactions, was used as the target level of theory for this work, with dispersion-corrected PM6-D3 as the semiempirical low level to incorporate the long-range interactions. Comparing directly to the experimental binding potencies, we obtain impressive correlations over all seven test sets, with an R
- Published
- 2018
46. Progress Toward Understanding the Molecular Details and Consequences of IgE-Receptor Crosslinking
- Author
-
David Holowka, Deborah Robertson, Barbara Baird, Patricia M. Kane, Byron Goldstein, Jon D. Erickson, and Anant K. Menon
- Subjects
biology ,Chemistry ,Immunology ,biology.protein ,Receptor ,Immunoglobulin E - Published
- 2018
47. Liver-Type Glutaminase is an Essential and Druggable Metabolic Node in Defined Breast Cancer Subtypes
- Author
-
Sekar Ramachandran, Zhihan-Emily Wang, Michael J. Lukey, Miao-chong J. Lin, Ahmad A. Cluntun, B. Blank, Jon W. Erickson, Richard A. Cerione, William P. Katt, and Joseph E. Druso
- Subjects
Citric acid cycle ,Breast cancer ,Downregulation and upregulation ,Glutaminase ,Cell growth ,medicine ,Cancer research ,Efflux ,Biology ,medicine.disease ,Carcinogenesis ,medicine.disease_cause ,Isozyme - Abstract
A key strategy targeting the metabolic changes underlying tumorigenesis involves inhibiting the glutaminase isozyme GLS to disrupt glutamine catabolism. However, identifying patient groups for this approach remains a challenge. Here, we define the roles of GLS and its less studied counterpart liver-type glutaminase (GLS2) in breast cancer. We find that GLS2 is upregulated and essential for TCA cycle anaplerosis, cell proliferation, and tumorigenesis in luminal-subtype breast cancers, which account for >70% of disease incidence, and that it mediates resistance to GLS-selective inhibitors. Although GLS is overexpressed in basal-subtype breast cancers, sensitivity to GLS inhibitors depends on glutamate efflux through the xCT antiporter. These findings establish an important role for GLS2 in tumorigenesis and suggest patient stratification approaches for glutaminase-targeted therapy.
- Published
- 2018
48. Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells
- Author
-
Scott M. Ulrich, Sekar Ramachandran, Richard A. Cerione, Jon W. Erickson, Clint A. Stalnecker, Mary Kate McBrayer, Yunxing Li, and Ralph J. DeBerardinis
- Subjects
Models, Molecular ,Glutamine ,Allosteric regulation ,Mice ,Enzyme activator ,Allosteric Regulation ,Tetramer ,Fluorescence Resonance Energy Transfer ,Animals ,Enzyme Inhibitors ,Protein Structure, Quaternary ,Transaminases ,Benzophenanthridines ,chemistry.chemical_classification ,Multidisciplinary ,Glutaminolysis ,biology ,Glutaminase ,Biological Sciences ,Recombinant Proteins ,Enzyme assay ,Cell Transformation, Neoplastic ,Enzyme ,Amino Acid Substitution ,Biochemistry ,chemistry ,Mutagenesis, Site-Directed ,biology.protein - Abstract
The mitochondrial enzyme glutaminase C (GAC) catalyzes the hydrolysis of glutamine to glutamate plus ammonia, a key step in the metabolism of glutamine by cancer cells. Recently, we discovered a class of allosteric inhibitors of GAC that inhibit cancer cell growth without affecting their normal cellular counterparts, with the lead compound being the bromo-benzophenanthridinone 968. Here, we take advantage of mouse embryonic fibroblasts transformed by oncogenic Dbl, which hyperactivates Rho GTPases, together with (13)C-labeled glutamine and stable-isotope tracing methods, to establish that 968 selectively blocks the enhancement in glutaminolysis necessary for satisfying the glutamine addiction of cancer cells. We then determine how 968 inhibits the catalytic activity of GAC. First, we developed a FRET assay to examine the effects of 968 on the ability of GAC to undergo the dimer-to-tetramer transition necessary for enzyme activation. We next demonstrate how the fluorescence of a reporter group attached to GAC provides a direct read-out of the binding of 968 and related compounds to the enzyme. By combining these fluorescence assays with newly developed GAC mutants trapped in either the monomeric or dimeric state, we show that 968 has the highest affinity for monomeric GAC and that the dose-dependent binding of 968 to GAC monomers directly matches its dose-dependent inhibition of enzyme activity and cellular transformation. Together, these findings highlight the requirement of tetramer formation as the mechanism of GAC activation and shed new light on how a distinct class of allosteric GAC inhibitors impacts the metabolic program of transformed cells.
- Published
- 2014
49. From Top-down to Participatory Planning: Conservation Lessons from the Adirondack Park, United States
- Author
-
Jon D. Erickson and Sabine U O’Hara
- Subjects
Participatory planning ,Geography ,business.industry ,Environmental resource management ,Resource management ,Top-down and bottom-up design ,business ,Environmental planning ,Innovation adoption - Published
- 2017
50. Fluorination at the 4 position alters the substrate behavior of L-glutamine and L-glutamate: Implications for positron emission tomography of neoplasias
- Author
-
Arthur J.L. Cooper, Juan A. Azcona, Jon W. Erickson, Hank F. Kung, Thomas M. Jeitner, Karl Ploessl, John T. Pinto, Eva Kristoferson, Clint A. Stalnecker, and Jianyong Li
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,biology ,Chemistry ,Stereochemistry ,Glutamate dehydrogenase ,Organic Chemistry ,Diastereomer ,Active site ,Substrate (chemistry) ,Biochemistry ,Article ,Inorganic Chemistry ,Glutamine ,03 medical and health sciences ,030104 developmental biology ,Enzyme ,In vivo ,Glutamine synthetase ,biology.protein ,Environmental Chemistry ,Physical and Theoretical Chemistry - Abstract
Two 4-fluoro-L-glutamine diastereoisomers [(2S,4R)-4-FGln, (2S,4S)-4-FGln] were previously developed for positron emission tomography. Label uptake into two tumor cell types was greater with [18F](2S,4R)-4-FGln than with [18F](2S,4S)-4-FGln. In the present work we investigated the enzymology of two diastereoisomers of 4-FGln, two diastereoisomers of 4-fluoroglutamate (4-FGlu) (potential metabolites of the 4-FGln diastereoisomers) and another fluoro-derivative of L-glutamine [(2S,4S)-4-(3-fluoropropyl)glutamine (FP-Gln)]. The two 4-FGlu diastereoisomers were found to be moderate-to-good substrates relative to L-glutamate of glutamate dehydrogenase, aspartate aminotransferase and alanine aminotransferase. Additionally, alanine aminotransferase was shown to catalyze an unusual γ-elimination reaction with both 4-FGlu diastereoisomers. Both 4-FGlu diastereoisomers were shown to be poor substrates, but strong inhibitors of glutamine synthetase. Both 4-FGln diastereoisomers were shown to be poor substrates compared to L-glutamine of glutamine transaminase L and α-aminoadipate aminotransferase. However, (2S,4R)-4-FGln was found to be a poor substrate of glutamine transaminase K, whereas (2S,4S)-4-FGln was shown to be an excellent substrate. By contrast, FP-Gln was found to be a poor substrate of all enzymes examined. Evidently, substitution of H in position 4 by F in L-glutamine/L-glutamate has moderate-to-profound effects on enzyme-catalyzed reactions. The present results: 1) show that 4-FGln and 4-FGlu diastereoisomers may be useful for studying active site topology of glutamate- and glutamine-utilizing enzymes; 2) provide a framework for understanding possible metabolic transformations in tumors of 18F-labeled (2S,4R)-4-FGln, (2S,4S)-4-FGln, (2S,4R)-4-FGlu or (2S,4S)-4-FGlu; and 3) show that [18F]FP-Gln is likely to be much less metabolically active in vivo than are the [18F]4-FGln diastereoisomers.
- Published
- 2017
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