6s43

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'''Unreleased structure'''
 
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The entry 6s43 is ON HOLD until Paper Publication
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==Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(5-(Azocan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide==
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<StructureSection load='6s43' size='340' side='right'caption='[[6s43]], [[Resolution|resolution]] 1.42&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6s43]] is a 4 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=6S43 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S43 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=KUE:~{N}-[5-(azocan-1-ylsulfonyl)-2-methoxy-phenyl]-2-(4-oxidanylidene-3~{H}-phthalazin-1-yl)ethanamide'>KUE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fum, fumC, DSI35_09545, ERS007663_02818, ERS007679_02635, ERS007688_02307, ERS007722_03256, ERS023446_00966, ERS024276_01230, ERS027646_00759, ERS027653_00188, ERS027654_00515, ERS027659_00384, ERS027661_00671, ERS027666_02275, ERS124361_03161, SAMEA2682864_03539, SAMEA2683035_02636 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fumarate_hydratase Fumarate hydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.2 4.2.1.2] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6s43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s43 OCA], [http://pdbe.org/6s43 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s43 RCSB], [http://www.ebi.ac.uk/pdbsum/6s43 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s43 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/A0A045IXZ8_MYCTX A0A045IXZ8_MYCTX]] Involved in the TCA cycle. Catalyzes the stereospecific interconversion of fumarate to L-malate.[HAMAP-Rule:MF_00743]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.
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Authors: Whitehouse, A.J., Libardo, M.D., Kasbekar, M., Brear, P., Fischer, G., Thomas, C.J., Barry, C.E., Boshoff, H.I., Coyne, A.G., Abell, C.
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Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode.,Whitehouse AJ, Libardo MDJ, Kasbekar M, Brear PD, Fischer G, Thomas CJ, Barry CE 3rd, Boshoff HIM, Coyne AG, Abell C J Med Chem. 2019 Dec 12;62(23):10586-10604. doi: 10.1021/acs.jmedchem.9b01203., Epub 2019 Sep 27. PMID:31517489<ref>PMID:31517489</ref>
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Description: Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(5-(Azocan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Thomas, C.J]]
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<div class="pdbe-citations 6s43" style="background-color:#fffaf0;"></div>
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[[Category: Kasbekar, M]]
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== References ==
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[[Category: Fischer, G]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Fumarate hydratase]]
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[[Category: Large Structures]]
[[Category: Abell, C]]
[[Category: Abell, C]]
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[[Category: Barry, C E]]
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[[Category: Boshoff, H I]]
[[Category: Brear, P]]
[[Category: Brear, P]]
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[[Category: Whitehouse, A.J]]
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[[Category: Coyne, A G]]
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[[Category: Coyne, A.G]]
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[[Category: Fischer, G]]
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[[Category: Libardo, M.D]]
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[[Category: Kasbekar, M]]
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[[Category: Boshoff, H.I]]
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[[Category: Libardo, M D]]
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[[Category: Barry, C.E]]
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[[Category: Thomas, C J]]
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[[Category: Whitehouse, A J]]
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[[Category: Fumarase]]
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[[Category: Lyase]]

Revision as of 13:16, 25 December 2019

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(5-(Azocan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide

PDB ID 6s43

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