期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 19, 页码 6548-6562出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm2003766
关键词
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资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- companies of the Industrial Macromolecular Crystallography Association through the Center for Advanced Radiation Sources at the University of Chicago, IL
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 gamma (RPTP gamma) 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 RPTP gamma, 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.
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