1p44: Difference between revisions

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New page: left|200px<br /><applet load="1p44" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p44, resolution 2.7Å" /> '''Targeting tuberculosi...
 
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[[Image:1p44.gif|left|200px]]<br /><applet load="1p44" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1p44, resolution 2.7&Aring;" />
'''Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data'''<br />


==Overview==
==Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data==
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.
<StructureSection load='1p44' size='340' side='right'caption='[[1p44]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<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='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='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='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>
</table>
== Function ==
[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/p4/1p44_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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>


==About this Structure==
==See Also==
1P44 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 GEQ 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=1P44 OCA].
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
 
__TOC__
==Reference==
</StructureSection>
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12606558 12606558]
[[Category: Large Structures]]
[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Single protein]]
[[Category: Alland D]]
[[Category: Alland, D.]]
[[Category: Fidock DA]]
[[Category: Fidock, D.A.]]
[[Category: Gourlie BB]]
[[Category: Gourlie, B.B.]]
[[Category: Gregory JS]]
[[Category: Gregory, J.S.]]
[[Category: Iwamoto H]]
[[Category: Iwamoto, H.]]
[[Category: Jacobs Jr WR]]
[[Category: Janjigian, A.D.]]
[[Category: Janjigian AD]]
[[Category: Jr, W.R.Jacobs.]]
[[Category: Kreiswirth B]]
[[Category: Kreiswirth, B.]]
[[Category: Kuo MR]]
[[Category: Kuo, M.R.]]
[[Category: Leonard M]]
[[Category: Leonard, M.]]
[[Category: Morbidoni HR]]
[[Category: Morbidoni, H.R.]]
[[Category: Musser JM]]
[[Category: Musser, J.M.]]
[[Category: Perozzo R]]
[[Category: Perozzo, R.]]
[[Category: Sacchettini JC]]
[[Category: Sacchettini, J.C.]]
[[Category: Sneddon SF]]
[[Category: Sneddon, S.F.]]
[[Category: Staveski MM]]
[[Category: Staveski, M.M.]]
[[Category: Yee C]]
[[Category: TBSGC, TB.Structural.Genomics.Consortium.]]
[[Category: Yee, C.]]
[[Category: GEQ]]
[[Category: NAD]]
[[Category: enoyl-acp reductase]]
[[Category: inha]]
[[Category: inhibitor]]
[[Category: protein structure initiative]]
[[Category: psi]]
[[Category: rossmann fold]]
[[Category: short chain dehydrogenase reductase]]
[[Category: structural genomics]]
[[Category: tb structural genomics consortium]]
[[Category: tbsgc]]
 
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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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