1p45
From Proteopedia
(New page: 200px<br /><applet load="1p45" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p45, resolution 2.60Å" /> '''Targeting tuberculos...) |
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| - | [[Image:1p45.gif|left|200px]]<br /><applet load="1p45" size=" | + | [[Image:1p45.gif|left|200px]]<br /><applet load="1p45" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1p45, resolution 2.60Å" /> | caption="1p45, resolution 2.60Å" /> | ||
'''Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data'''<br /> | '''Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Tuberculosis and malaria together result in an estimated 5 million deaths | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1P45 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 TCL 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:// | + | 1P45 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 <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=TCL:'>TCL</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1P45 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Alland, D.]] | [[Category: Alland, D.]] | ||
| - | [[Category: Fidock, D | + | [[Category: Fidock, D A.]] |
| - | [[Category: Gourlie, B | + | [[Category: Gourlie, B B.]] |
| - | [[Category: Gregory, J | + | [[Category: Gregory, J S.]] |
[[Category: Iwamoto, H.]] | [[Category: Iwamoto, H.]] | ||
| - | [[Category: Janjigian, A | + | [[Category: Janjigian, A D.]] |
| - | [[Category: Jr., W | + | [[Category: Jr., W R.Jacobs.]] |
| - | [[Category: Kreiswirth, B | + | [[Category: Kreiswirth, B N.]] |
| - | [[Category: Kuo, M | + | [[Category: Kuo, M R.]] |
[[Category: Leonard, M.]] | [[Category: Leonard, M.]] | ||
| - | [[Category: Morbidoni, H | + | [[Category: Morbidoni, H R.]] |
| - | [[Category: Musser, J | + | [[Category: Musser, J M.]] |
[[Category: Perozzo, R.]] | [[Category: Perozzo, R.]] | ||
| - | [[Category: Sacchettini, J | + | [[Category: Sacchettini, J C.]] |
| - | [[Category: Sneddon, S | + | [[Category: Sneddon, S F.]] |
| - | [[Category: Staveski, M | + | [[Category: Staveski, M M.]] |
| - | [[Category: TBSGC, TB | + | [[Category: TBSGC, TB Structural Genomics Consortium.]] |
[[Category: Yee, C.]] | [[Category: Yee, C.]] | ||
[[Category: NAD]] | [[Category: NAD]] | ||
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[[Category: triclosan]] | [[Category: triclosan]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:24:53 2008'' |
Revision as of 12:24, 21 February 2008
|
Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data
Overview
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.
About this Structure
1P45 is a Single protein structure of sequence from Mycobacterium tuberculosis with and as ligands. Active as [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 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 [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
Page seeded by OCA on Thu Feb 21 14:24:53 2008
Categories: Mycobacterium tuberculosis | Single protein | Alland, D. | Fidock, D A. | Gourlie, B B. | Gregory, J S. | Iwamoto, H. | Janjigian, A D. | Jr., W R.Jacobs. | Kreiswirth, B N. | Kuo, M R. | Leonard, M. | Morbidoni, H R. | Musser, J M. | Perozzo, R. | Sacchettini, J C. | Sneddon, S F. | Staveski, M M. | TBSGC, TB Structural Genomics Consortium. | Yee, C. | NAD | TCL | Enoyl-acp reductase | Inha | Protein structure initiative | Psi | Rossmann fold | Short chain dehydrogenase reductase | Structural genomics | Tb structural genomics consortium | Tbsgc | Triclosan
