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| - | [[Image:2h7m.jpg|left|200px]]<br /><applet load="2h7m" size="450" color="white" frame="true" align="right" spinBox="true" | + | #REDIRECT [[4tzk]] This PDB entry is obsolete and replaced by 4tzk |
| - | caption="2h7m, resolution 1.62Å" />
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| - | '''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with 1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide'''<br />
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| - | ==Overview==
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| - | In view of the worldwide spread of multidrug resistance of Mycobacterium, tuberculosis, there is an urgent need to discover antituberculosis agent, with novel structures. InhA, the enoyl acyl carrier protein reductase, (ENR) from M. tuberculosis, is one of the key enzymes involved in the, mycobacterial fatty acid elongation cycle and has been validated as an, effective antimicrobial target. We report here the discovery, through, high-throughput screening, of a series of pyrrolidine carboxamides as a, novel class of potent InhA inhibitors. Crystal structures of InhA, complexed with three inhibitors have been used to elucidate the inhibitor, binding mode. The potency of the lead compound was improved over 160-fold, by subsequent optimization through iterative microtiter library synthesis, followed by in situ activity screening without purification. Resolution of, racemic mixtures of several inhibitors indicate that only one enantiomer, is active as an inhibitor of InhA.
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| - | ==About this Structure==
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| - | 2H7M is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with NAD and 641 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2H7M OCA].
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| - | ==Reference==
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| - | Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17034137 17034137]
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| - | [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
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| - | [[Category: Mycobacterium tuberculosis]]
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| - | [[Category: Single protein]]
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| - | [[Category: Alian, A.]]
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| - | [[Category: He, X.]]
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| - | [[Category: Montellano, P.R.Ortiz.de.]]
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| - | [[Category: Stroud, R.]]
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| - | [[Category: 641]]
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| - | [[Category: NAD]]
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| - | [[Category: enoyl acyl carrier reductase]]
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| - | [[Category: inha]]
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| - | [[Category: oxidoreductase]]
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| - | [[Category: pyrrolidine carboxamide]]
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| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 11:35:23 2007''
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