1p44: Difference between revisions

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<StructureSection load='1p44' size='340' side='right'caption='[[1p44]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='1p44' size='340' side='right'caption='[[1p44]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1p44]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1P44 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1P44 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1p44]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1P44 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1P44 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEQ:5-{[4-(9H-FLUOREN-9-YL)PIPERAZIN-1-YL]CARBONYL}-1H-INDOLE'>GEQ</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">INHA OR RV1484 OR MT1531 OR MTCY277.05 OR MB1520 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEQ:5-{[4-(9H-FLUOREN-9-YL)PIPERAZIN-1-YL]CARBONYL}-1H-INDOLE'>GEQ</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1p44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1p44 OCA], [https://pdbe.org/1p44 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1p44 RCSB], [https://www.ebi.ac.uk/pdbsum/1p44 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1p44 ProSAT], [https://www.topsan.org/Proteins/TBSGC/1p44 TOPSAN]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1p44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1p44 OCA], [http://pdbe.org/1p44 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1p44 RCSB], [http://www.ebi.ac.uk/pdbsum/1p44 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1p44 ProSAT], [http://www.topsan.org/Proteins/TBSGC/1p44 TOPSAN]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU]
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1p44 ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1p44 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.
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<ref>PMID:12606558</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1p44" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Alland, D]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Fidock, D A]]
[[Category: Alland D]]
[[Category: Gourlie, B B]]
[[Category: Fidock DA]]
[[Category: Gregory, J S]]
[[Category: Gourlie BB]]
[[Category: Iwamoto, H]]
[[Category: Gregory JS]]
[[Category: Janjigian, A D]]
[[Category: Iwamoto H]]
[[Category: Jr, W R.Jacobs]]
[[Category: Jacobs Jr WR]]
[[Category: Kreiswirth, B]]
[[Category: Janjigian AD]]
[[Category: Kuo, M R]]
[[Category: Kreiswirth B]]
[[Category: Leonard, M]]
[[Category: Kuo MR]]
[[Category: Morbidoni, H R]]
[[Category: Leonard M]]
[[Category: Musser, J M]]
[[Category: Morbidoni HR]]
[[Category: Perozzo, R]]
[[Category: Musser JM]]
[[Category: Sacchettini, J C]]
[[Category: Perozzo R]]
[[Category: Sneddon, S F]]
[[Category: Sacchettini JC]]
[[Category: Staveski, M M]]
[[Category: Sneddon SF]]
[[Category: Structural genomic]]
[[Category: Staveski MM]]
[[Category: Yee, C]]
[[Category: Yee C]]
[[Category: Enoyl-acp reductase]]
[[Category: Inha]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase]]
[[Category: PSI, Protein structure initiative]]
[[Category: Rossmann fold]]
[[Category: Short chain dehydrogenase reductase]]
[[Category: Tbsgc]]

Latest revision as of 08:05, 14 February 2024

Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data

1p44, resolution 2.70Å

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