1p45

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Revision as of 21:20, 20 November 2007

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spinqualitylabelsall models 1p45, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data

Overview

Tuberculosis and malaria together result in an estimated 5 million deaths, annually. The spread of multidrug resistance in the most pathogenic, causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory, properties. Although genetically unrelated, both organisms use a type II, fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a, key type II enzyme, has been repeatedly validated as an effective, antimicrobial target. Using high throughput inhibitor screens with a, combinatorial library, we have identified two novel classes of compounds, with activity against the M. tuberculosis and P. falciparum enzyme, (referred to as InhA and PfENR, respectively). The crystal structure of, InhA complexed with NAD+ and one of the inhibitors was determined to, elucidate the mode of binding. Structural analysis of InhA with the broad, spectrum antimicrobial triclosan revealed a unique stoichiometry where the, enzyme contained either a single triclosan molecule, in a configuration, typical of other bacterial ENR:triclosan structures, or harbored two, triclosan molecules bound to the active site. Significantly, these, compounds do not require activation and are effective against wild-type, and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of, inhibitor binding to InhA for subsequent chemical optimization.

About this Structure

1P45 is a Single protein structure of sequence from Mycobacterium tuberculosis with NAD and TCL as ligands. Active as [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 Full crystallographic information is available from OCA.

Reference

Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data., Kuo MR, Morbidoni HR, Alland D, Sneddon SF, Gourlie BB, Staveski MM, Leonard M, Gregory JS, Janjigian AD, Yee C, Musser JM, Kreiswirth B, Iwamoto H, Perozzo R, Jacobs WR Jr, Sacchettini JC, Fidock DA, J Biol Chem. 2003 Jun 6;278(23):20851-9. Epub 2003 Feb 26. PMID:12606558 [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]

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