Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
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.
Grundner
Christoph
C
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Perrin
Dominique
D
Hooft van Huijsduijnen
Rob
R
Swinnen
Dominique
D
Gonzalez
Jérome
J
Gee
Christine L
CL
Wells
Timothy N
TN
Alber
Tom
T
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
D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D017027:Protein Tyrosine Phosphatases