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| {{STRUCTURE_2aqh| PDB=2aqh | SCENE= }} | | {{STRUCTURE_2aqh| PDB=2aqh | SCENE= }} |
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| '''Crystal structure of Isoniazid-resistant I21V Enoyl-ACP(CoA) reductase mutant enzyme from Mycobacterium tuberculosis in complex with NADH'''
| | ===Crystal structure of Isoniazid-resistant I21V Enoyl-ACP(CoA) reductase mutant enzyme from Mycobacterium tuberculosis in complex with NADH=== |
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| ==Overview==
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| An understanding of isoniazid (INH) drug resistance mechanism in Mycobacterium tuberculosis should provide significant insight for the development of newer anti-tubercular agents able to control INH-resistant tuberculosis (TB). The inhA-encoded 2-trans enoyl-acyl carrier protein reductase enzyme (InhA) has been shown through biochemical and genetic studies to be the primary target for INH. In agreement with these results, mutations in the inhA structural gene have been found in INH-resistant clinical isolates of M.tuberculosis, the causative agent of TB. In addition, the InhA mutants were shown to have higher dissociation constant values for NADH and lower values for the apparent first-order rate constant for INH inactivation as compared to wild-type InhA. Here, in trying to identify structural changes between wild-type and INH-resistant InhA enzymes, we have solved the crystal structures of wild-type and of S94A, I47T and I21V InhA proteins in complex with NADH to resolutions of, respectively, 2.3A, 2.2A, 2.0 A, and 1.9A. The more prominent structural differences are located in, and appear to indirectly affect, the dinucleotide binding loop structure. Moreover, studies on pre-steady-state kinetics of NADH binding have been carried out. The results showed that the limiting rate constant values for NADH dissociation from the InhA-NADH binary complexes (k(off)) were eleven, five, and tenfold higher for, respectively, I21V, I47T, and S94A INH-resistant mutants of InhA as compared to INH-sensitive wild-type InhA. Accordingly, these results are proposed to be able to account for the reduction in affinity for NADH for the INH-resistant InhA enzymes.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16647717}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16647717 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16647717}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Souza, O N.de.]] | | [[Category: Souza, O N.de.]] |
| [[Category: Enoyl-acyl carrier protein]] | | [[Category: Enoyl-acyl carrier protein]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:20:58 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 17:04:21 2008'' |