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27 results on '"LeMotte, Peter"'

7. Kinetic analysis of estrogen receptor/ ligand interactions

Author

Rich, Rebecca L., Hoth, Lise R., Geoghegan, Kieran F., Brown, Thomas A., LeMotte, Peter K., Simons, Samuel P., Hensley, Preston, and Myszka, David G.

Subjects
Estrogen -- Receptors, Ligand binding (Biochemistry) -- Research, Biosensors -- Research, Science and technology
Abstract

Surface plasmon resonance biosensor technology was used to directly measure the binding interactions of small molecules to the ligand-binding domain of human estrogen receptor. In a screening mode, specific ligands of the receptor were easily discerned from nonligands. In a high-resolution mode, the association and dissociation phase binding responses were shown to be reproducible and could be fit globally to a simple interaction model to extract reaction rate constants. On average, antagonist ligands (such as tamoxifen and nafoxidine) were observed to bind to the receptor with association rates that were 500-fold slower than agonists (such as estriol and [beta]-estradiol). This finding is consistent with these antagonists binding to an altered conformation of the receptor. The biosensor assay also could identify subtle differences in how the same ligand interacted with two different isoforms of the receptor ([alpha] and [beta]). The biosensor's ability to determine kinetic rate constants for small molecule/protein interactions provides unique opportunities to understand the mechanisms associated with complex formation as well as new information to drive the optimization of drug candidates.

Published
2002

9. Marked resistance of RARgamma-deficient mice to the toxic effects of retinoic acid

Author

Look, Jutta, Landwehr, Jorg, Bauer, Franz, Hoffmann, Anne Schmitt, Bluethmann, Horst, and Lemotte, Peter

Subjects
Tretinoin -- Health aspects, Mice, mutant strains -- Usage, Biological sciences
Abstract

Homozygous mutant mice are found to be resistant to four times the retinoic acid dose given to the wild type mice indicating that RARgamma has a major role to play in neutralizing the retinoid toxicity. Thus the excessive intake of retinoic acid resulting in toxic effects causing hypervitaminosis A is preventable using RARgamma. This has practical usage in clinical labs in reducing the toxicity of synthetic retinoids.

Published
1995

11. What The Structure Of Human Liver Glycogen Phosphorylase A Tells Us About Its Regulation

Author

RATH, VIRGINIA L., AMMIRATI, MARK L., DANLEY, DENNIS E., FENNELL, KIMBERLY F., HYNES, THOMAS R., LEMOTTE, PETER K., MANSOUR, MAHMOUD N., SCHULTE, GAYLE K., WASILKO, DAVID J., and PANDIT, JAYVARDHAN

Subjects
Liver -- Glycogenic function, Glycogen metabolism -- Physiological aspects, Health
Abstract

Total hepatic glucose output is the sm of the activities of glycogen phosphorylase and glycogen synthase. Maintaining tight control of blood glucose levels has been shown to be critical in [...]

Published
2000

12. Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung

Author

Danahay, Henry, primary, Pessotti, Angelica D., additional, Coote, Julie, additional, Montgomery, Brooke E., additional, Xia, Donghui, additional, Wilson, Aaron, additional, Yang, Haidi, additional, Wang, Zhao, additional, Bevan, Luke, additional, Thomas, Chris, additional, Petit, Stephanie, additional, London, Anne, additional, LeMotte, Peter, additional, Doelemeyer, Arno, additional, Vélez-Reyes, Germán L., additional, Bernasconi, Paula, additional, Fryer, Christy J., additional, Edwards, Matt, additional, Capodieci, Paola, additional, Chen, Amy, additional, Hild, Marc, additional, and Jaffe, Aron B., additional

Published
2015
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13. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R‐spondin

Author

Xie, Yang, primary, Zamponi, Raffaella, additional, Charlat, Olga, additional, Ramones, Melissa, additional, Swalley, Susanne, additional, Jiang, Xiaomo, additional, Rivera, Daniel, additional, Tschantz, William, additional, Lu, Bo, additional, Quinn, Lisa, additional, Dimitri, Chris, additional, Parker, Jefferson, additional, Jeffery, Doug, additional, Wilcox, Sheri K, additional, Watrobka, Mike, additional, LeMotte, Peter, additional, Granda, Brian, additional, Porter, Jeffrey A, additional, Myer, Vic E, additional, Loew, Andreas, additional, and Cong, Feng, additional

Published
2013
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15. Phosphorylation of serine residues in histidine-tag sequences attached to recombinant protein kinases: A cause of heterogeneity in mass and complications in function

Author

Du, Ping, primary, Loulakis, Pat, additional, Luo, Chun, additional, Mistry, Anil, additional, Simons, Samuel P., additional, LeMotte, Peter K., additional, Rajamohan, Francis, additional, Rafidi, Kristina, additional, Coleman, Kevin G., additional, Geoghegan, Kieran F., additional, and Xie, Zhi, additional

Published
2005
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16. Theoretical and Experimental Design of Atypical Kinase Inhibitors: Application to p38 MAP Kinase

Author

McClure, Kim F., primary, Abramov, Yuriy A., additional, Laird, Ellen R., additional, Barberia, John T., additional, Cai, Weiling, additional, Carty, Thomas J., additional, Cortina, Santo R., additional, Danley, Dennis E., additional, Dipesa, Alan J., additional, Donahue, Kathleen M., additional, Dombroski, Mark A., additional, Elliott, Nancy C., additional, Gabel, Christopher A., additional, Han, Seungil, additional, Hynes, Thomas R., additional, LeMotte, Peter K., additional, Mansour, Mahmoud N., additional, Marr, Eric S., additional, Letavic, Michael A., additional, Pandit, Jayvardhan, additional, Ripin, David B., additional, Sweeney, Francis J., additional, Tan, Douglas, additional, and Tao, Yong, additional

Published
2005
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17. Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TRβ subtype-selective thyromimetics

Author

Dow, Robert L., primary, Schneider, Steven R., additional, Paight, Ernest S., additional, Hank, Richard F., additional, Chiang, Phoebe, additional, Cornelius, Peter, additional, Lee, Eunsun, additional, Newsome, William P., additional, Swick, Andrew G., additional, Spitzer, Josephine, additional, Hargrove, Diane M., additional, Patterson, Terrell A., additional, Pandit, Jayvardhan, additional, Chrunyk, Boris A., additional, LeMotte, Peter K., additional, Danley, Dennis E., additional, Rosner, Michele H., additional, Ammirati, Mark J., additional, Simons, Samuel P., additional, Schulte, Gayle K., additional, Tate, Bonnie F., additional, and DaSilva-Jardine, Paul, additional

Published
2003
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22. Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

Author

Bernasconi-Elias, Paula, Hu, Tiancen, Jenkins, David, Firestone, Brant, Gans, Sara, Kurth, Esther, Capodieci, Paola, Deplazes-Lauber, Joelle, Petropoulos, Konstantin, Thiel, Phillip, Ponsel, Dirk, Choi, Sung Hee, LeMotte, Peter, London, Anne, Goetcshkes, Margaret, Nolin, Erin, Jones, Michael D., Slocum, Kelly, Kluk, Michael J., Weinstock, David M., Christodoulou, Alexandra, Weinberg, Olga, Jaehrling, Jan, Ettenberg, Seth A., Buckler, Alan, Blacklow, Stephen C., Aster, Jon C., and Fryer, Christy J.

Subjects
Notch signaling, NOTCH3, T-ALL, inhibitory antibody
Abstract

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that two of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, two of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.

Published
2016
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24. Structural basis for the catalytic mechanism of human phosphodiesterase 9.

Author

Shenping Liu, Mansour, Mahmoud N., Diliman, Keith S., Perez, Jose R., Danley, Dennis E., Aeed, Paul A., Simons, Samuel P., LeMotte, Peter K., and Menniti, Frank S.

Subjects
PHOSPHODIESTERASES, ENZYMES, CRYSTALLOGRAPHY, HYDROLYSIS, INTERMEDIATES (Chemistry)
Abstract

The phosphodiesterases (PDEs) are metal ion-dependent enzymes that regulate cellular signaling by metabolic inactivation of the ubiquitous second messengers cAMP and cGMP. In this role, the PDEs are involved in many biological and metabolic processes and are proven targets of successful drugs for the treatments of a wide range of diseases. However, because of the rapidity of the hydrolysis reaction, an experimental knowledge of the enzymatic mechanisms of the PDEs at the atomic level is still lacking. Here, we report the structures of reaction intermediates accumulated at the reaction steady state in PDE9/crystal and preserved by freeze-trapping. These structures reveal the catalytic process of a PDE and explain the substrate specificity of PDE9 in an actual reaction and the cation requirements of POEs in general. [ABSTRACT FROM AUTHOR]

Published
2008
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27. Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.

Author

Dow RL, Schneider SR, Paight ES, Hank RF, Chiang P, Cornelius P, Lee E, Newsome WP, Swick AG, Spitzer J, Hargrove DM, Patterson TA, Pandit J, Chrunyk BA, LeMotte PK, Danley DE, Rosner MH, Ammirati MJ, Simons SP, Schulte GK, Tate BF, and DaSilva-Jardine P

Subjects
Crystallography, X-Ray, Drug Design, Humans, Indicators and Reagents, Ligands, Models, Molecular, Molecular Mimicry, Protein Binding, Protein Conformation, Structure-Activity Relationship, Uracil pharmacology, Receptors, Thyroid Hormone drug effects, Thyroid Hormones pharmacology, Uracil analogs & derivatives, Uracil chemistry
Abstract

In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.

Published
2003
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