25 results on '"Anil K. Padyana"'
Search Results
2. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
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Christopher E. Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Sebastian Hayes, Zi Peng Fan, Eric L. Allen, Ying Chen, Lingling Huang, Meina Liu, Yingjia Zhang, Gabrielle McDonald, Rohini Narayanaswamy, Sung Choe, Yue Chen, Stefan Gross, Giovanni Cianchetta, Anil K. Padyana, Stuart Murray, Wei Liu, Kevin M. Marks, Joshua Murtie, Marion Dorsch, Shengfang Jin, Nelamangala Nagaraja, Scott A. Biller, Thomas Roddy, Janeta Popovici-Muller, and Gromoslaw A. Smolen
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Science - Abstract
Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.
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- 2019
- Full Text
- View/download PDF
3. Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase
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Anil K. Padyana, Stefan Gross, Lei Jin, Giovanni Cianchetta, Rohini Narayanaswamy, Feng Wang, Rui Wang, Cheng Fang, Xiaobing Lv, Scott A. Biller, Lenny Dang, Christopher E. Mahoney, Nelamangala Nagaraja, David Pirman, Zhihua Sui, Janeta Popovici-Muller, and Gromoslaw A. Smolen
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Science - Abstract
Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.
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- 2019
- Full Text
- View/download PDF
4. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
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Brandon M. Gassaway, Rebecca L. Cardone, Anil K. Padyana, Max C. Petersen, Evan T. Judd, Sebastian Hayes, Shuilong Tong, Karl W. Barber, Maria Apostolidi, Abudukadier Abulizi, Joshua B. Sheetz, Kshitiz, Hans R. Aerni, Stefan Gross, Charles Kung, Varman T. Samuel, Gerald I. Shulman, Richard G. Kibbey, and Jesse Rinehart
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Biology (General) ,QH301-705.5 - Abstract
Summary: Pyruvate kinase is an important enzyme in glycolysis and a key metabolic control point. We recently observed a pyruvate kinase liver isoform (PKL) phosphorylation site at S113 that correlates with insulin resistance in rats on a 3 day high-fat diet (HFD) and suggests additional control points for PKL activity. However, in contrast to the classical model of PKL regulation, neither authentically phosphorylated PKL at S12 nor S113 alone is sufficient to alter enzyme kinetics or structure. Instead, we show that cyclin-dependent kinases (CDKs) are activated by the HFD and responsible for PKL phosphorylation at position S113 in addition to other targets. These CDKs control PKL nuclear retention, alter cytosolic PKL activity, and ultimately influence glucose production. These results change our view of PKL regulation and highlight a previously unrecognized pathway of hepatic CDK activity and metabolic control points that may be important in insulin resistance and type 2 diabetes. : Gassaway et al. identify a diet-induced, cyclin-dependent kinase-regulated phosphorylation site at S113 on pyruvate kinase. Although they determine that neither phosphorylation of this site nor the canonical PKA-regulated S12 site directly impacts enzyme kinetics, they demonstrate that S113 phosphorylation alters pyruvate kinase subcellular localization and influences glucose production. Keywords: pyruvate kinase, cyclin-dependent kinase, metabolism, phosphorylation, hepatic glucose production, enzyme regulation, insulin resistance, sub-cellular localization, nuclear localization
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- 2019
- Full Text
- View/download PDF
5. Supplementary Data Table S3 from Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
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Danielle B. Ulanet, Kevin M. Marks, Josh Murtie, Scott A. Biller, Jonathan Hurov, Georg Lenz, Lenny Dang, Nelamangala Nagaraja, Zhihua Sui, Sreevalsam Gopinath, Thomas Antony, Sunil K. Panigrahi, K. Satish Reddy, Hosahalli Subramanya, Siva Sanjeeva Rao, Kavitha Nellore, Mark Fletcher, Sebastian Hayes, Alan Mann, Tabea Erdmann, Zi-Peng Fan, Charles Locuson, Sebastien Ronseaux, Lei Jin, Anil K. Padyana, Erin Artin, Mya Steadman, Sung Choe, Rohini Narayanaswamy, Kevin Truskowski, John Coco, Victor Chubukov, and Gabrielle McDonald
- Abstract
GO analysis of proteins with at least a 1.5-fold increase in expression in the presence of AG-636 compared to DMSO
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- 2023
6. Supplementary Data from Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
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Danielle B. Ulanet, Kevin M. Marks, Josh Murtie, Scott A. Biller, Jonathan Hurov, Georg Lenz, Lenny Dang, Nelamangala Nagaraja, Zhihua Sui, Sreevalsam Gopinath, Thomas Antony, Sunil K. Panigrahi, K. Satish Reddy, Hosahalli Subramanya, Siva Sanjeeva Rao, Kavitha Nellore, Mark Fletcher, Sebastian Hayes, Alan Mann, Tabea Erdmann, Zi-Peng Fan, Charles Locuson, Sebastien Ronseaux, Lei Jin, Anil K. Padyana, Erin Artin, Mya Steadman, Sung Choe, Rohini Narayanaswamy, Kevin Truskowski, John Coco, Victor Chubukov, and Gabrielle McDonald
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Supplementary methods, references and figures
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- 2023
7. Data from Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
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Danielle B. Ulanet, Kevin M. Marks, Josh Murtie, Scott A. Biller, Jonathan Hurov, Georg Lenz, Lenny Dang, Nelamangala Nagaraja, Zhihua Sui, Sreevalsam Gopinath, Thomas Antony, Sunil K. Panigrahi, K. Satish Reddy, Hosahalli Subramanya, Siva Sanjeeva Rao, Kavitha Nellore, Mark Fletcher, Sebastian Hayes, Alan Mann, Tabea Erdmann, Zi-Peng Fan, Charles Locuson, Sebastien Ronseaux, Lei Jin, Anil K. Padyana, Erin Artin, Mya Steadman, Sung Choe, Rohini Narayanaswamy, Kevin Truskowski, John Coco, Victor Chubukov, and Gabrielle McDonald
- Abstract
Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.
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- 2023
8. Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion
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Joshua Murtie, Anil K. Padyana, Lei Jin, Marc L. Hyer, Zhixiao Liu, Scott A. Biller, Jeremy Travins, Amelia Barnett, Katya Marjon, Brandon Nicolay, Wentao Wei, Raj Nagaraja, Cheng Fang, Yi Gao, Yabo Sun, Ye Zhixiong, Fan Jiang, Peter Kalev, Stefan Gross, Zenon D. Konteatis, Byron DeLaBarre, Zhihua Sui, Kevin Marks, Lenny Dang, Jie Yu, Everton Mandley, and Yue Chen
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chemistry.chemical_classification ,0303 health sciences ,Methionine ,Allosteric regulation ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Enzyme ,chemistry ,CDKN2A ,Methionine Adenosyltransferase ,Drug Discovery ,Cancer cell ,Cancer research ,Molecular Medicine ,Structure–activity relationship ,Binding site ,030304 developmental biology - Abstract
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
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- 2021
9. Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads
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Mingzong Li, Zenon Konteatis, Nelamangala Nagaraja, Yue Chen, Shubao Zhou, Guangning Ma, Stefan Gross, Katya Marjon, Marc L. Hyer, Everton Mandley, Max Lein, Anil K. Padyana, Lei Jin, Shuilong Tong, Rachel Peters, Joshua Murtie, Jeremy Travins, Matthew Medeiros, Peng Liu, Victoria Frank, Evan T. Judd, Scott A. Biller, Kevin M. Marks, Zhihua Sui, and Samuel K. Reznik
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S-Adenosylmethionine ,Drug Design ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Brain ,Humans ,Methionine Adenosyltransferase - Abstract
Inhibition of the
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- 2022
10. Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
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Brandon Nicolay, Ingo K. Mellinghoff, Paolo Codega, Hua Yang, Zenon D. Konteatis, Janeta Popovici-Muller, Katharine E. Yen, Rohini Narayaraswamy, Raj Nagaraja, Zhihua Sui, Shinsan M. Su, Erin Artin, Kimberly Straley, Zhenwei Cai, Feng Wang, Shuilong Tong, Lei Jin, Yue Chen, Cui Dawei, Carl Campos, Zhiyong Luo, Cheng Fang, Xiaobing Lv, Lenny Dang, Ding Zhou, Anil K. Padyana, Huachun Tang, and Scott A. Biller
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chemistry.chemical_classification ,IDH1 ,Organic Chemistry ,Mutant ,Dual inhibitor ,2-hydroxyglutarate ,medicine.disease ,Biochemistry ,Featured Letter ,Isocitrate dehydrogenase ,vorasidenib ,chemistry.chemical_compound ,Enzyme ,AG-881 ,chemistry ,Glioma ,Drug Discovery ,medicine ,Cancer research ,Binding site ,mutant IDH1/mIDH2 ,Penetrant (biochemical) - Abstract
Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.
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- 2020
11. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
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Lingling Huang, Kevin Marks, Shengfang Jin, Sung Choe, Scott A. Biller, Joshua Murtie, Gromoslaw A. Smolen, Janeta Popovici-Muller, Eric L. Allen, Rohini Narayanaswamy, Stefan Gross, Yingjia Zhang, Wei Liu, Thomas P. Roddy, Gabrielle McDonald, Nelamangala Nagaraja, Marion Dorsch, Anil K. Padyana, Christopher E. Mahoney, Taryn Sleger, Meina Liu, Yue Chen, Stuart Murray, Victor Chubukov, Sebastian Hayes, Giovanni Cianchetta, Ying Chen, Zi Peng Fan, and David Pirman
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0301 basic medicine ,Squalene monooxygenase ,Science ,Cell ,Chemical biology ,General Physics and Astronomy ,Antineoplastic Agents ,02 engineering and technology ,Neuroendocrine tumors ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Drug Delivery Systems ,Cell Line, Tumor ,medicine ,Humans ,lcsh:Science ,Regulation of gene expression ,Multidisciplinary ,Cancer ,General Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cholesterol ,Squalene Monooxygenase ,Cell culture ,Cancer cell ,Cancer research ,lcsh:Q ,Drug Screening Assays, Antitumor ,0210 nano-technology ,Gene Deletion - Abstract
Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers., Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.
- Published
- 2019
12. Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous
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Zenon, Konteatis, Jeremy, Travins, Stefan, Gross, Katya, Marjon, Amelia, Barnett, Everton, Mandley, Brandon, Nicolay, Raj, Nagaraja, Yue, Chen, Yabo, Sun, Zhixiao, Liu, Jie, Yu, Zhixiong, Ye, Fan, Jiang, Wentao, Wei, Cheng, Fang, Yi, Gao, Peter, Kalev, Marc L, Hyer, Byron, DeLaBarre, Lei, Jin, Anil K, Padyana, Lenny, Dang, Joshua, Murtie, Scott A, Biller, Zhihua, Sui, and Kevin M, Marks
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S-Adenosylmethionine ,Structure-Activity Relationship ,Binding Sites ,Purine-Nucleoside Phosphorylase ,Drug Design ,Neoplasms ,Homozygote ,Humans ,Methionine Adenosyltransferase ,Enzyme Inhibitors ,Molecular Dynamics Simulation ,Crystallography, X-Ray - Abstract
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (
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- 2021
13. High-throughput mutagenesis reveals unique structural features of human ADAR1
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Carlito B. Lebrilla, Yixuan Xie, Agya Karki, Peter A. Beal, SeHee Park, Fang Fang, Justin B. Siegel, Erin E Doherty, Anil K. Padyana, and Yue Zhang
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0301 basic medicine ,Molecular biology ,Adenosine Deaminase ,Science ,Protein domain ,General Physics and Astronomy ,Mutagenesis (molecular biology technique) ,Computational biology ,Biology ,medicine.disease_cause ,Biochemistry ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Rare Diseases ,Protein Domains ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,lcsh:Science ,Gene ,Mutation ,Multidisciplinary ,Binding Sites ,030102 biochemistry & molecular biology ,Rational design ,RNA ,RNA-Binding Proteins ,General Chemistry ,Chemical biology ,RNA silencing ,Zinc ,030104 developmental biology ,RNA editing ,Mutagenesis ,lcsh:Q ,Structural biology - Abstract
Adenosine Deaminases that act on RNA (ADARs) are enzymes that catalyze adenosine to inosine conversion in dsRNA, a common form of RNA editing. Mutations in the human ADAR1 gene are known to cause disease and recent studies have identified ADAR1 as a potential therapeutic target for a subset of cancers. However, efforts to define the mechanistic effects for disease associated ADAR1 mutations and the rational design of ADAR1 inhibitors are limited by a lack of structural information. Here, we describe the combination of high throughput mutagenesis screening studies, biochemical characterization and Rosetta-based structure modeling to identify unique features of ADAR1. Importantly, these studies reveal a previously unknown zinc-binding site on the surface of the ADAR1 deaminase domain which is important for ADAR1 editing activity. Furthermore, we present structural models that explain known properties of this enzyme and make predictions about the role of specific residues in a surface loop unique to ADAR1., Human ADAR proteins are responsible for RNA editing, conversion of adenosine to inosine in double-stranded RNA. Here the authors report a previously unknown zinc ion-binding site in the catalytic domain of human ADAR1 using high throughput mutagenesis, biochemical assay and Rosetta-based protein structure modeling.
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- 2020
14. Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
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K. Satish Reddy, Scott A. Biller, Kavitha Nellore, Siva Sanjeeva Rao, Anil K. Padyana, Georg Lenz, Thomas Antony, Charles Locuson, Jonathan Hurov, Mya Steadman, Tabea Erdmann, Mark Fletcher, Zi Peng Fan, Kevin Truskowski, Sreevalsam Gopinath, Alan Mann, Danielle Ulanet, Rohini Narayanaswamy, Sebastien Ronseaux, Gabrielle McDonald, Sung Choe, Zhihua Sui, John Coco, Lenny Dang, Kevin Marks, Victor Chubukov, Erin Artin, Sebastian Hayes, Josh Murtie, Lei Jin, Nelamangala Nagaraja, Hosahalli Subramanya, and Sunil Kumar Panigrahi
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0301 basic medicine ,Proteomics ,Cancer Research ,Oxidoreductases Acting on CH-CH Group Donors ,Cell Survival ,Chemical biology ,Dihydroorotate Dehydrogenase ,Antineoplastic Agents ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Extracellular ,Humans ,Enzyme Inhibitors ,Neoplasm Staging ,Genomics ,medicine.disease ,Uridine ,Lymphoma ,Metabolic pathway ,030104 developmental biology ,Pyrimidines ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Cancer research ,Dihydroorotate dehydrogenase ,DNA Damage - Abstract
Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.
- Published
- 2020
15. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
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Olivia Bawa, Monika Pilichowska, Paule Opolon, Jeffrey O. Saunders, Fang Wang, Cyril Quivoron, Anil K. Padyana, Zenon D. Konteatis, Kimberly Straley, Erica Tobin, Sophie Broutin, Marion Dorsch, Hua Yang, Byron DeLaBarre, Jeremy Travins, Sung Choe, Yue Chen, Lei Jin, Wentao Wei, Virginie Penard-Lacronique, Raj Nagaraja, Wei Liu, Lenny Dang, Shengfang Jin, Cheng Fang, Lee Silverman, Fan Jiang, Katharine E. Yen, Giovanni Cianchetta, Olivier Bernard, Erin Artin, Muriel D. David, Shin-San Michael Su, Stefan Gross, Francesco G. Salituro, Véronique Saada, Stéphane de Botton, Scott A. Biller, Angelo Paci, Benoit S. Marteyn, Yingxia Xu, Agios Pharmaceuticals, Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Plateforme d’évaluation préclinique (PFEP), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de thérapie cellulaire, Département de médecine oncologique [Gustave Roussy], Pathogénie microbienne moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Tufts Medical Center, ShangPharma, Viva Biotech Ltd., and This work was funded by Agios Pharmaceuticals, Inc., the French National Institute of Health (INSERM-AVIESAN), the National Cancer Institute (INCa-DGOS-Inserm_6043 and INCa 2012-1-RT-09), and the Fondation Association pour la Recherche sur le Cancer (ARC, SL220130607089 Programme Labellisé to V. Penard-Lacronique and S. de Botton). M.D. David is funded by a fellowship from the Institut National du Cancer (INCa-DGOS_5733).
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0301 basic medicine ,Myeloid ,IDH1 ,Cellular differentiation ,Myeloid leukemia ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Enasidenib ,medicine.disease ,Molecular biology ,IDH2 ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,medicine - Abstract
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies. Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR. See related commentary by Thomas and Majeti, p. 459. See related article by Shih et al., p. 494. This article is highlighted in the In This Issue feature, p. 443
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- 2017
16. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
- Author
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Charles Kung, Sebastian Hayes, Jesse Rinehart, Evan T. Judd, Hans R. Aerni, Shuilong Tong, Joshua B. Sheetz, Richard G. Kibbey, Stefan Gross, Rebecca L. Cardone, Abudukadier Abulizi, Kshitiz, Maria Apostolidi, Brandon M. Gassaway, Karl W. Barber, Gerald I. Shulman, Anil K. Padyana, Max C. Petersen, and Varman T. Samuel
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Male ,0301 basic medicine ,Pyruvate Kinase ,Diet, High-Fat ,Article ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Cyclin-dependent kinase ,Cell Line, Tumor ,medicine ,Animals ,Glycolysis ,Phosphorylation ,lcsh:QH301-705.5 ,Cells, Cultured ,biology ,Kinase ,Chemistry ,Gluconeogenesis ,Metabolism ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Cyclin-Dependent Kinases ,Rats ,Cell biology ,Glucose ,030104 developmental biology ,lcsh:Biology (General) ,Hepatocytes ,biology.protein ,Insulin Resistance ,Signal transduction ,030217 neurology & neurosurgery ,Pyruvate kinase ,Signal Transduction - Abstract
Summary: Pyruvate kinase is an important enzyme in glycolysis and a key metabolic control point. We recently observed a pyruvate kinase liver isoform (PKL) phosphorylation site at S113 that correlates with insulin resistance in rats on a 3 day high-fat diet (HFD) and suggests additional control points for PKL activity. However, in contrast to the classical model of PKL regulation, neither authentically phosphorylated PKL at S12 nor S113 alone is sufficient to alter enzyme kinetics or structure. Instead, we show that cyclin-dependent kinases (CDKs) are activated by the HFD and responsible for PKL phosphorylation at position S113 in addition to other targets. These CDKs control PKL nuclear retention, alter cytosolic PKL activity, and ultimately influence glucose production. These results change our view of PKL regulation and highlight a previously unrecognized pathway of hepatic CDK activity and metabolic control points that may be important in insulin resistance and type 2 diabetes. : Gassaway et al. identify a diet-induced, cyclin-dependent kinase-regulated phosphorylation site at S113 on pyruvate kinase. Although they determine that neither phosphorylation of this site nor the canonical PKA-regulated S12 site directly impacts enzyme kinetics, they demonstrate that S113 phosphorylation alters pyruvate kinase subcellular localization and influences glucose production. Keywords: pyruvate kinase, cyclin-dependent kinase, metabolism, phosphorylation, hepatic glucose production, enzyme regulation, insulin resistance, sub-cellular localization, nuclear localization
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- 2019
17. Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop
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Oliver S. Smart, Paul Emsley, Cary B. Bauer, David A. Case, John L. Markley, Joseph Marcotrigiano, Jasmine Young, Atsushi Nakagawa, Seth F. Harris, Haruki Nakamura, Wolfram Tempel, Radka Svobodová, T. Krojer, Pamela A. Williams, Robert T. Nolte, Catherine E. Peishoff, Jorg Hendle, Chenghua Shao, Jeff Blaney, Dale E. Tronrud, Paul D. Adams, Randy J. Read, Marc C. Nicklaus, Kirk Clark, Helen M. Berman, Jeffrey A. Bell, Evan E Bolton, Suzanna C. Ward, Stephen K. Burley, Alan E. Mark, Garib N. Murshudov, Victoria A. Feher, Matthew T. Miller, John Spurlino, Sameer Velankar, Steven Sheriff, Tom Darden, Wladek Minor, Talapady N. Bhat, John D. Westbrook, Gerard J. Kleywegt, Terry R. Stouch, Huanwang Yang, Gérard Bricogne, Thomas C. Terwilliger, Anil K. Padyana, Zukang Feng, Colin R. Groom, Andrzej Joachimiak, David G. Brown, Anthony Nicholls, Gaetano T. Montelione, Thomas Holder, Kathleen Aertgeerts, Stephen M. Soisson, Gregory L. Warren, Susan Pieniazek, Read, Randy [0000-0001-8273-0047], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Models, Molecular ,Protein Conformation ,Complex formation ,Protein Data Bank (RCSB PDB) ,Biophysics ,Crystallographic data ,Guidelines as Topic ,010402 general chemistry ,Crystallography, X-Ray ,Ligands ,01 natural sciences ,Article ,03 medical and health sciences ,Structural bioinformatics ,Databases ,Extant taxon ,Structural Biology ,Models ,Information and Computing Sciences ,Databases, Protein ,Molecular Biology ,Data Curation ,Crystallography ,Ligand ,Chemistry ,Protein ,Molecular ,Proteins ,computer.file_format ,Collaboratory ,Biological Sciences ,Protein Data Bank ,Data science ,0104 chemical sciences ,030104 developmental biology ,Generic Health Relevance ,QD431 ,Chemical Sciences ,X-Ray ,computer - Abstract
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent\ud an important source of information concerning drug-target interactions, providing atomic level insights\ud into the physical chemistry of complex formation between macromolecules and ligands. Of the\ud more than 115,000 entries extant in the Protein Data Bank (PDB) archive, ~75% include at least one non-polymeric\ud ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug\ud discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across\ud the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic\ud Data Center/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop\ud held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30–31, 2015.\ud Experts in protein crystallography from academe and industry came together with non-profit and for-profit\ud software providers for crystallography and with experts in computational chemistry and data archiving to\ud discuss and make recommendations on best practices, as framed by a series of questions central to structural\ud studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived\ud in the PDB? How should the ligands be best represented? How should structural models of macromoleculeligand\ud complexes be validated? What supplementary information should accompany publications of structural\ud studies of biological macromolecules? Consensus recommendations on best practices developed in\ud response to each of these questions are provided, together with some details regarding implementation.\ud Important issues addressed but not resolved at the workshop are also enumerated.
- Published
- 2016
18. Abstract 3504: A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition
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Gromoslaw A. Smolen, Stefan Gross, Shengfang Jin, Scott A. Biller, Taryn Sleger, Sung Choe, Rohini Narayanaswamy, Joshua Murtie, Raj Nagaraja, Gabrielle McDonald, Thomas P. Roddy, Yu Chen, David Pirman, Giovanni Cianchetta, Christopher E. Mahoney, Sebastian Hayes, Zi Peng Fan, Anil K. Padyana, Stuart Murray, and Victor Chubukov
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Cancer Research ,Oncology ,Neuroendocrine Cancer ,Chemical biology ,Vulnerability ,Computational biology ,Biology - Abstract
Numerous reports have described the differential metabolism of cancer cells as compared to their normal counterparts. However, only relatively few metabolic genes with cancer-specific mutations have been reported and the identification of cancer subsets with particular metabolic vulnerabilities remains a challenge. To explore potential cancer-specific dependencies, we conducted a chemical biology screen utilizing a collection of small molecule inhibitors targeting diverse metabolic pathways in a large panel of cancer cell lines. A subset of neuroendocrine tumors, particularly small cell lung cancers (SCLC), displayed a striking dependence on squalene epoxygenase, SQLE, an enzyme in the cholesterol biosynthetic pathway. To develop further confidence in these findings, we have determined the first three-dimensional SQLE structure and further advanced a pharmacological toolbox for SQLE. Using these tools, we showed that the observed effects are on target and that the patterns of cellular sensitivity observed in vitro display excellent translation to in vivo xenografts studies. Interestingly, using a variety of orthogonal approaches, we demonstrated that SQLE sensitivity appears not to be related to overall inhibition of the cholesterol pathway but rather to specific and toxic accumulation of the SQLE substrate, squalene. Collectively, these findings highlight the utility of chemical biology screens and identify SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly SCLC. Citation Format: Christopher Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Anil Padyana, Stefan Gross, Sebastian Hayes, Zi Peng Fan, Gabrielle McDonald, Yu Chen, Joshua Murtie, Giovanni Cianchetta, Raj Nagaraja, Rohini Narayanaswamy, Sung Choe, Stuart Murray, Shengfang Jin, Scott Biller, Thomas Roddy, Gromoslaw A. Smolen. A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3504.
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- 2018
19. Structural Basis for Autoinhibition and Mutational Activation of Eukaryotic Initiation Factor 2α Protein Kinase GCN2*[boxs]
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Stephen K. Burley, Antonina Roll-Mecak, Anil K. Padyana, Alan G. Hinnebusch, and Hongfang Qiu
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Models, Molecular ,Saccharomyces cerevisiae Proteins ,Protein Conformation ,Molecular Sequence Data ,Saccharomyces cerevisiae ,Protein Serine-Threonine Kinases ,Biology ,Arginine ,Crystallography, X-Ray ,Biochemistry ,eIF-2 Kinase ,Adenosine Triphosphate ,Eukaryotic translation ,Protein structure ,RNA, Transfer ,Eukaryotic initiation factor ,Escherichia coli ,Histidine ,Magnesium ,Amino Acid Sequence ,Phosphorylation ,Binding site ,Protein kinase A ,Molecular Biology ,eIF2 ,Binding Sites ,Sequence Homology, Amino Acid ,Prokaryotic initiation factor-2 ,Hydrolysis ,Cell Biology ,TRNA binding ,Protein Structure, Tertiary ,Mutation ,Biophysics ,Dimerization ,Protein Kinases ,Protein Binding - Abstract
The GCN2 protein kinase coordinates protein synthesis with levels of amino acid stores by phosphorylating eukaryotic translation initiation factor 2. The autoinhibited form of GCN2 is activated in cells starved of amino acids by binding of uncharged tRNA to a histidyl-tRNA synthetase-like domain. Replacement of Arg-794 with Gly in the PK domain (R794G) activates GCN2 independently of tRNA binding. Crystal structures of the GCN2 protein kinase domain have been determined for wild-type and R794G mutant forms in the apo state and bound to ATP/AMPPNP. These structures reveal that GCN2 autoinhibition results from stabilization of a closed conformation that restricts ATP binding. The R794G mutant shows increased flexibility in the hinge region connecting the N- and C-lobes, resulting from loss of multiple interactions involving Arg794. This conformational change is associated with intradomain movement that enhances ATP binding and hydrolysis. We propose that intramolecular interactions following tRNA binding remodel the hinge region in a manner similar to the mechanism of enzyme activation elicited by the R794G mutation.
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- 2005
20. Crystal Structure of Shikimate 5-Dehydrogenase (SDH) Bound to NADP
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Anil K. Padyana and Stephen K. Burley
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chemistry.chemical_classification ,0303 health sciences ,Methanococcus ,Materials science ,biology ,Stereochemistry ,030302 biochemistry & molecular biology ,Active site ,Dehydrogenase ,biology.organism_classification ,Cofactor ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Oxidoreductase ,Structural Biology ,biology.protein ,Aromatic amino acids ,Homology modeling ,Molecular Biology ,Nicotinamide adenine dinucleotide phosphate ,030304 developmental biology - Abstract
The crystal structure of Methanococcus jannaschii shikimate 5-dehydrogenase ( Mj SDH) bound to the cofactor nicotinamide adenine dinucleotide phosphate (NADP) has been determined at 2.35 A resolution. Shikimate 5-dehydrogenase (SDH) is responsible for NADP-dependent catalysis of the fourth step in shikimate biosynthesis, which is essential for aromatic amino acid metabolism in bacteria, microbial eukaryotes, and plants. The structure of Mj SDH is a compact α/β sandwich with two distinct domains, responsible for binding substrate and the NADP cofactor, respectively. A phylogenetically conserved deep cleft on the protein surface corresponds to the enzyme active site. The structure reveals a topologically new domain fold within the N-terminal segment of the polypeptide chain, which binds substrate and supports dimerization. Insights gained from homology modeling and sequence/structure comparisons suggest that the SDHs represent a unique class of dehydrogenases. The structure provides a framework for further investigation to discover and develop novel inhibitors targeting this essential enzyme.
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- 2003
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21. Role of a two-residue spacer in an ?,?-didehydrophenylalanine containing hexapeptide: crystal and solution structure of Boc-Val-?Phe-Leu-Ala-?Phe-Ala-OMe
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Virander S. Chauhan, N. R. Jagannathan, Puniti Mathur, Suryanarayanarao Ramakumar, and Anil K. Padyana
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Pharmacology ,chemistry.chemical_classification ,Stereochemistry ,Hydrogen bond ,Organic Chemistry ,Peptide ,General Medicine ,Crystal structure ,Biochemistry ,Acceptor ,Residue (chemistry) ,chemistry ,Structural Biology ,310 helix ,Drug Discovery ,Proton NMR ,Molecular Medicine ,Molecule ,Molecular Biology - Abstract
The peptide Boc-Val1-ΔPhe2-Leu3-Ala4-ΔPhe5-Ala6-OMe has been examined for the structural consequence of placing a two-residue segment between the ΔPhe residues. The peptide is stabilized by four consecutive β-turns. The overall conformation of the molecule is a right-handed 310-helix, with average (ϕ, ψ) values (−67.7°, −22.7°), unwound at the C-terminus. The 1H NMR results also suggest that the peptide maintains its 310-helical structure in solution as observed in the crystal state. The crystal structure is stabilized through head-to-tail hydrogen bonds and a repertoire of aromatic interactions laterally directed between adjacent helices, which are antiparallel to each other. The aromatic ring of ΔPhe5 forms the hub of multicentred interactions, namely as a donor in aromatic C–H···π and aromatic C–H···OC interactions and as an acceptor in a CH3···π interaction. The present structure uniquely illustrates the unusual capability of a ΔPhe ring to host such concerted interactions and suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
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- 2003
22. Role of a two-residue spacer in an alpha,beta-Didehydrophenylalanine containing hexapeptide: crystal and solution structure of Boc-val-deltaPhe-Leu-Ala-deltaPhe-Ala-OMe
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Anil K, Padyana, S, Ramakumar, Puniti, Mathur, N R, Jagannathan, and V S, Chauhan
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Magnetic Resonance Spectroscopy ,Protein Conformation ,Circular Dichroism ,Phenylalanine ,Crystallography, X-Ray ,Peptides - Abstract
The peptide Boc-Val1-deltaPhe2-Leu3-Ala4-deltaPhe5-Ala6-OMe has been examined for the structural consequence of placing a two-residue segment between the deltaPhe residues. The peptide is stabilized by four consecutive beta-turns. The overall conformation of the molecule is a right-handed 3(10)-helix, with average (phi, psi) values (-67.7 degrees, -22.7 degrees), unwound at the C-terminus. The 1H NMR results also suggest that the peptide maintains its 3(10)-helical structure in solution as observed in the crystal state. The crystal structure is stabilized through head-to-tail hydrogen bonds and a repertoire of aromatic interactions laterally directed between adjacent helices, which are antiparallel to each other. The aromatic ring of deltaPhe5 forms the hub of multicentred interactions, namely as a donor in aromatic C-H...pi and aromatic C-H...O=C interactions and as an acceptor in a CH3...pi interaction. The present structure uniquely illustrates the unusual capability of a deltaPhe ring to host such concerted interactions and suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures.
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- 2003
23. Crystal structure of a light-harvesting protein C-phycocyanin from Spirulina platensis
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Anil K. Padyana, Vadiraja B. Bhat, Suryanarayanarao Ramakumar, K.M. Madyastha, and K.R. Rajashankar
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Models, Molecular ,Materials science ,Physics ,Phycobiliprotein ,Organic Chemistry ,Biophysics ,Phycocyanin ,Cell Biology ,Crystal structure ,Random hexamer ,Crystallography, X-Ray ,Cyanobacteria ,Biochemistry ,Protein Structure, Secondary ,Crystal ,Crystallography ,chemistry.chemical_compound ,Protein Subunits ,chemistry ,Phycocyanobilin ,BioInformatics Centre ,Molecular replacement ,Bilin ,Molecular Biology - Abstract
The crystal structure of C-phycocyanin, a light-harvesting phycobiliprotein from cyanobacteria (blue-green algae) Spirulina platensis has been solved by molecular replacement technique. The crystals belong to space group $P2_1$ with cell parameters a = 107.20, b = 115.40, c = 183.04 \AA; $\beta=90.2^o$. The structure has been refined to a crystallographic R factor of 19.2% $(R_{free}=23.9$%) using the X-ray diffraction data extending up to 2.2 \AA resolution. The asymmetric unit of the crystal cell consists of two $(\alpha \beta)_6$-hexamers, each hexamer being the functional unit in the native antenna rod of cyanobacteria. The molecular structure resembles that of other reported C-phycocyanins. However, the unique form of aggregation of two $(\alpha \beta)_6$-hexamers in the crystal asymmetric unit, suggests additional pathways of energy transfer in lateral direction between the adjacent hexamers involving $\beta 155$ phycocyanobilin chromophores.
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- 2001
24. Fragment-Based Discoveryof Indole Inhibitors of MatrixMetalloproteinase-13.
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Steven J. Taylor, Asitha Abeywardane, Shuang Liang, Ingo Muegge, Anil K. Padyana, Zhaoming Xiong, Melissa Hill-Drzewi, Bennett Farmer, Xiang Li, Brandon Collins, JohnXiang Li, Alexander Heim-Riether, John Proudfoot, Qiang Zhang, Daniel Goldberg, Ljiljana Zuvela-Jelaska, Hani Zaher, Jun Li, and Neil A. Farrow
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- 2011
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25. Lateral energy transfer model for adjacent light-harvesting antennae rods of C-phycocyanins
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Suryanarayanarao Ramakumar and Anil K. Padyana
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Models, Molecular ,Light-harvesting ,Phycocyanobilin ,Light-Harvesting Protein Complexes ,Molecular Conformation ,Biophysics ,macromolecular substances ,Crystal structure ,Random hexamer ,Biochemistry ,Molecular physics ,Rod ,Bacterial Proteins ,BioInformatics Centre ,Spirulina ,Phycobilisomes ,Photosynthesis ,Chemistry ,Physics ,Phycocyanin ,Resonance ,Cell Biology ,Chromophore ,Crystallography ,Energy Transfer ,Phycobilisome ,Antenna (radio) ,Excitation - Abstract
Modeling of excitation transfer pathways have been carried out for the structure of Spirulina platensis C-phycocyanin. Calculations by Förster mechanism using the crystal structure coordinates determined in our laboratory indicate ultra-fast lateral energy transfer rates between pairs of chromophores attached to two adjacent hexamer disks. The pairwise transfer times of the order of a few pico-seconds correspond to resonance transitions between peripheral β155 chromophores. A quantitative lateral energy transfer model for C-phycocyanin light-harvesting antenna rods that is suggestive to its native structural organization emerges from this study.
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- View/download PDF
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