title: Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
abstract: Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.
authors.affiliation: Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. pauljala@gmail.com
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Milton C
authors.initials: MC
authors.lastname: Hillman
authors.forename: Mary
authors.initials: M
authors.lastname: Becker-Pasha
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Brian G
authors.initials: BG
authors.lastname: Reid
authors.forename: Ronald
authors.initials: R
authors.lastname: Klabe
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Brian
authors.initials: B
authors.lastname: Wayland
authors.forename: Brent
authors.initials: B
authors.lastname: Douty
authors.forename: Padmaja
authors.initials: P
authors.lastname: Polam
authors.forename: Zelda
authors.initials: Z
authors.lastname: Wasserman
authors.forename: Michael
authors.initials: M
authors.lastname: Bower
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Hollis
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D063065:Organophosphonates / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D063065:Organophosphonates; D013844:Thiazoles; C512915:isothiazolidinone; D014867:Water; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases