2h7n
From Proteopedia
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| - | [[Image:2h7n.jpg|left|200px]] | + | [[Image:2h7n.jpg|left|200px]] |
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| - | '''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide''' | + | {{Structure |
| + | |PDB= 2h7n |SIZE=350|CAPTION= <scene name='initialview01'>2h7n</scene>, resolution 1.9Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene> and <scene name='pdbligand=744:(3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE'>744</scene> | ||
| + | |ACTIVITY= [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] | ||
| + | |GENE= inhA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis]) | ||
| + | }} | ||
| + | |||
| + | '''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2H7N is a [ | + | 2H7N is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA]. |
==Reference== | ==Reference== | ||
| - | 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:// | + | 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://www.ncbi.nlm.nih.gov/pubmed/17034137 17034137] |
[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]] | [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]] | ||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
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[[Category: pyrrolidine carboxamide]] | [[Category: pyrrolidine carboxamide]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:13:41 2008'' |
Revision as of 15:13, 20 March 2008
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| , resolution 1.9Å | |||||||
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| Ligands: | and | ||||||
| Gene: | inhA (Mycobacterium tuberculosis) | ||||||
| Activity: | [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide
Overview
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.
About this Structure
2H7N is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
Reference
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:17034137 [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
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