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Title: Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan-Proline-Aspartate (WPD) Loop

Abstract

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an 'open' conformation or a 'closed' conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced 'superopen' conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. BMS
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1049581
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 54; Journal Issue: (19) ; 10, 2011; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CATALYSIS; CHAINS; CLOSURES; PHOSPHATASES; PROTEINS; RESIDUES; TYROSINE

Citation Formats

Sheriff, Steven, Beno, Brett R, Zhai, Weixu, Kostich, Walter A, McDonnell, Patricia A, Kish, Kevin, Goldfarb, Valentina, Gao, Mian, Kiefer, Susan E, Yanchunas, Joseph, Huang, Yanling, Shi, Shuhao, Zhu, Shirong, Dzierba, Carolyn, Bronson, Joanne, Macor, John E, Appiah, Kingsley K, Westphal, Ryan S, O’Connell, Jonathan, and Gerritz, Samuel W. Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan-Proline-Aspartate (WPD) Loop. United States: N. p., 2012. Web. doi:10.1021/jm2003766.
Sheriff, Steven, Beno, Brett R, Zhai, Weixu, Kostich, Walter A, McDonnell, Patricia A, Kish, Kevin, Goldfarb, Valentina, Gao, Mian, Kiefer, Susan E, Yanchunas, Joseph, Huang, Yanling, Shi, Shuhao, Zhu, Shirong, Dzierba, Carolyn, Bronson, Joanne, Macor, John E, Appiah, Kingsley K, Westphal, Ryan S, O’Connell, Jonathan, & Gerritz, Samuel W. Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan-Proline-Aspartate (WPD) Loop. United States. doi:10.1021/jm2003766.
Sheriff, Steven, Beno, Brett R, Zhai, Weixu, Kostich, Walter A, McDonnell, Patricia A, Kish, Kevin, Goldfarb, Valentina, Gao, Mian, Kiefer, Susan E, Yanchunas, Joseph, Huang, Yanling, Shi, Shuhao, Zhu, Shirong, Dzierba, Carolyn, Bronson, Joanne, Macor, John E, Appiah, Kingsley K, Westphal, Ryan S, O’Connell, Jonathan, and Gerritz, Samuel W. Fri . "Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan-Proline-Aspartate (WPD) Loop". United States. doi:10.1021/jm2003766.
@article{osti_1049581,
title = {Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan-Proline-Aspartate (WPD) Loop},
author = {Sheriff, Steven and Beno, Brett R and Zhai, Weixu and Kostich, Walter A and McDonnell, Patricia A and Kish, Kevin and Goldfarb, Valentina and Gao, Mian and Kiefer, Susan E and Yanchunas, Joseph and Huang, Yanling and Shi, Shuhao and Zhu, Shirong and Dzierba, Carolyn and Bronson, Joanne and Macor, John E and Appiah, Kingsley K and Westphal, Ryan S and O’Connell, Jonathan and Gerritz, Samuel W},
abstractNote = {Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an 'open' conformation or a 'closed' conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced 'superopen' conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.},
doi = {10.1021/jm2003766},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = (19) ; 10, 2011,
volume = 54,
place = {United States},
year = {2012},
month = {11}
}