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: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States. steven.sheriff@bms.com
authors: Steven
authors: S
authors: Sheriff
authors: Brett R
authors: BR
authors: Beno
authors: Weixu
authors: W
authors: Zhai
authors: Walter A
authors: WA
authors: Kostich
authors: Patricia A
authors: PA
authors: McDonnell
authors: Kevin
authors: K
authors: Kish
authors: Valentina
authors: V
authors: Goldfarb
authors: Mian
authors: M
authors: Gao
authors: Susan E
authors: SE
authors: Kiefer
authors: Joseph
authors: J
authors: Yanchunas
authors: Yanling
authors: Y
authors: Huang
authors: Shuhao
authors: S
authors: Shi
authors: Shirong
authors: S
authors: Zhu
authors: Carolyn
authors: C
authors: Dzierba
authors: Joanne
authors: J
authors: Bronson
authors: John E
authors: JE
authors: Macor
authors: Kingsley K
authors: KK
authors: Appiah
authors: Ryan S
authors: RS
authors: Westphal
authors: Jonathan
authors: J
authors: O'Connell
authors: Samuel W
authors: SW
authors: Gerritz
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D008024:Ligands; D013876:Thiophenes; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5