title: Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
abstract: Tyrosine kinases and phosphatases establish the crucial balance of tyrosine phosphorylation in cellular signaling, but creating specific inhibitors of protein Tyr phosphatases (PTPs) remains a challenge. Here, we report the development of a potent, selective inhibitor of Mycobacterium tuberculosis PtpB, a bacterial PTP that is secreted into host cells where it disrupts unidentified signaling pathways. The inhibitor, (oxalylamino-methylene)-thiophene sulfonamide (OMTS), showed an IC(50) of 440 +/- 50 nM and >60-fold specificity for PtpB over six human PTPs. The 2 A resolution crystal structure of PtpB in complex with OMTS revealed a large rearrangement of the enzyme, with some residues shifting >27 A relative to the PtpB:PO(4) complex. Extensive contacts with the catalytic loop provide a potential basis for inhibitor selectivity. Two OMTS molecules bound adjacent to each other, raising the possibility of a second substrate phosphotyrosine binding site in PtpB. The PtpB:OMTS structure provides an unanticipated framework to guide inhibitor improvement.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors: Christoph
authors: C
authors: Grundner
authors: Dominique
authors: D
authors: Perrin
authors: Rob
authors: R
authors: Hooft van Huijsduijnen
authors: Dominique
authors: D
authors: Swinnen
authors: Jérome
authors: J
authors: Gonzalez
authors: Christine L
authors: CL
authors: Gee
authors: Timothy N
authors: TN
authors: Wells
authors: Tom
authors: T
authors: Alber
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D017027:Protein Tyrosine Phosphatases