2OZ5

Crystal structure of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB in complex with the specific inhibitor OMTS

Summary for 2OZ5

• Entry DOI: 10.2210/pdb2oz5/pdb
• Descriptor: Phosphotyrosine protein phosphatase ptpb, {(3-CHLOROBENZYL)[(5-{[(3,3-DIPHENYLPROPYL)AMINO]SULFONYL}-2-THIENYL)METHYL]AMINO}(OXO)ACETIC ACID (3 entities in total)
• Functional Keywords: protein tyrosine phosphatase in complex with small molecule inhibitor, structural genomics, tb structural genomics consortium, tbsgc, unknown function
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 67062.85

Authors

Grundner, C.,Gee, C.L.,Alber, T.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2007-02-23, release date: 2007-05-01, Last modification date: 2024-02-21)

Primary citation

Grundner, C.,Perrin, D.,Hooft van Huijsduijnen, R.,Swinnen, D.,Gonzalez, J.,Gee, C.L.,Wells, T.N.,Alber, T.
Structural Basis for Selective Inhibition of Mycobacterium tuberculosis Protein Tyrosine Phosphatase PtpB.
Structure, 15:499-509, 2007

PubMed 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.

PubMed: 17437721
DOI: 10.1016/j.str.2007.03.003

Experimental method

X-RAY DIFFRACTION (2 Å)