1w2h
From Proteopedia
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CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH AZIDOTHYMIDINE MONOPHOSPHATE (AZT-MP) (2.0 A RESOLUTION)
Overview
Tuberculosis (TB) is the primary cause of mortality among infectious, diseases. Mycobacterium tuberculosis thymidylate kinase (TMPK(Mtub)), catalyzes the ATP-dependent phosphorylation of deoxythymidine, 5'-monophosphate (dTMP). Essential to DNA replication, this enzyme, represents a promising target for developing new drugs against TB, because, the configuration of its active site is unique within the TMPK family., Indeed, it has been proposed that, as opposed to other TMPKs, catalysis by, TMPK(Mtub) necessitates the transient binding of a magnesium ion, coordinating the phosphate acceptor. Moreover, 3'-azidodeoxythymidine, monophosphate (AZTMP) is a competitive inhibitor of TMPK(Mtub), whereas it, is a substrate for human and other TMPKs. Here, the crystal structures of, TMPK(Mtub) in complex with deoxythymidine (dT) and AZTMP were determined, to 2.1 and 2.0 A resolution, respectively, and suggest a mechanism for, inhibition. The azido group of AZTMP perturbs the induced-fit mechanism, normally adopted by the enzyme. Magnesium is prevented from binding, and, the resulting electrostatic environment precludes phosphoryl transfer from, occurring. Our data provide a model for drug development against, tuberculosis.
About this Structure
1W2H is a Single protein structure of sequence from Mycobacterium tuberculosis with ACT, ATM and ATM as ligands. Active as dTMP kinase, with EC number 2.7.4.9 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
Reference
The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition., Fioravanti E, Adam V, Munier-Lehmann H, Bourgeois D, Biochemistry. 2005 Jan 11;44(1):130-7. PMID:15628853
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