6s43: Difference between revisions

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'''Unreleased structure'''


The entry 6s43 is ON HOLD  until Paper Publication
==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==
<StructureSection load='6s43' size='340' side='right'caption='[[6s43]], [[Resolution|resolution]] 1.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6s43]] is a 4 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=6S43 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S43 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]] 1.42&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6s43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s43 OCA], [https://pdbe.org/6s43 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s43 RCSB], [https://www.ebi.ac.uk/pdbsum/6s43 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s43 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FUMC_MYCTU FUMC_MYCTU] Catalyzes the reversible addition of water to fumarate to give L-malate.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


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.
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>


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
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Thomas, C.J]]
<div class="pdbe-citations 6s43" style="background-color:#fffaf0;"></div>
[[Category: Kasbekar, M]]
 
[[Category: Fischer, G]]
==See Also==
[[Category: Abell, C]]
*[[Fumarase|Fumarase]]
[[Category: Brear, P]]
== References ==
[[Category: Whitehouse, A.J]]
<references/>
[[Category: Coyne, A.G]]
__TOC__
[[Category: Libardo, M.D]]
</StructureSection>
[[Category: Boshoff, H.I]]
[[Category: Large Structures]]
[[Category: Barry, C.E]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Abell C]]
[[Category: Barry CE]]
[[Category: Boshoff HI]]
[[Category: Brear P]]
[[Category: Coyne AG]]
[[Category: Fischer G]]
[[Category: Kasbekar M]]
[[Category: Libardo MD]]
[[Category: Thomas CJ]]
[[Category: Whitehouse AJ]]
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