Small Molecule Receptor Protein Tyrosine Phosphatase 纬 (RPTP纬) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan鈥揚roline鈥揂spartate (WPD) Loop

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• 作者：Steven Sheriff ; Brett R. Beno ; Weixu Zhai ; Walter A. Kostich ; Patricia A. McDonnell ; Kevin Kish ; Valentina Goldfarb ; Mian Gao ; Susan E. Kiefer ; Joseph Yanchunas ; Yanling Huang ; Shuhao Shi ; Shirong Zhu ; Carolyn Dzierba ; Joanne Bronson ; John E. Macor ; Kingsley K. Appiah ; Ryan S. Westphal ; Jonathan O鈥機onnell ; Samuel W. Gerritz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6548-6562
• 全文大小：1373K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan鈥損roline鈥揳spartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an 鈥渙pen鈥?conformation or a 鈥渃losed鈥?conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase 纬 (RPTP纬) revealed a ligand-induced 鈥渟uperopen鈥?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 RPTP纬, 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.