1p45

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{{STRUCTURE_1p45| PDB=1p45 | SCENE= }}
{{STRUCTURE_1p45| PDB=1p45 | SCENE= }}
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'''Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data'''
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===Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_12606558}}
==About this Structure==
==About this Structure==
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[[Category: Tbsgc]]
[[Category: Tbsgc]]
[[Category: Triclosan]]
[[Category: Triclosan]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 14:54:21 2008''

Revision as of 11:54, 27 July 2008

Image:1p45.png

Template:STRUCTURE 1p45

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

Template:ABSTRACT PUBMED 12606558

About this Structure

1P45 is a Single protein structure of sequence from Mycobacterium tuberculosis. 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

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