2aqh: Difference between revisions

Revision as of 19:20, 3 May 2008

Crystal structure of Isoniazid-resistant I21V Enoyl-ACP(CoA) reductase mutant enzyme from Mycobacterium tuberculosis in complex with NADH

OverviewOverview

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.

About this StructureAbout this Structure

2AQH is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.

ReferenceReference

Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase enzymes from Mycobacterium tuberculosis., Oliveira JS, Pereira JH, Canduri F, Rodrigues NC, de Souza ON, de Azevedo WF Jr, Basso LA, Santos DS, J Mol Biol. 2006 Jun 9;359(3):646-66. Epub 2006 Apr 21. PMID:16647717 Page seeded by OCA on Sat May 3 19:20:58 2008

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OCA

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 [[Image:2aqh.gif|left|200px]]
- {{Structure
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-|PDB= 2aqh |SIZE=350|CAPTION= <scene name='initialview01'>2aqh</scene>, resolution 2.01&Aring;
+The line below this paragraph, containing "STRUCTURE_2aqh", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_2aqh|  PDB=2aqh  |  SCENE=  }}
-|RELATEDENTRY=[[2aqi|2AQI]], [[2aqk|2AQK]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2aqh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aqh OCA], [http://www.ebi.ac.uk/pdbsum/2aqh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2aqh RCSB]</span>
-}}
 '''Crystal structure of Isoniazid-resistant I21V Enoyl-ACP(CoA) reductase mutant enzyme from Mycobacterium tuberculosis in complex with NADH'''
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 ==Reference==
 Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase enzymes from Mycobacterium tuberculosis., Oliveira JS, Pereira JH, Canduri F, Rodrigues NC, de Souza ON, de Azevedo WF Jr, Basso LA, Santos DS, J Mol Biol. 2006 Jun 9;359(3):646-66. Epub 2006 Apr 21. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16647717 16647717]
-[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
 [[Category: Mycobacterium tuberculosis]]
 [[Category: Single protein]]
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 [[Category: Santos, D S.]]
 [[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 Mon Mar 31 01:55:57 2008''