5w2q: Difference between revisions
New page: '''Unreleased structure''' The entry 5w2q is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures |
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==Crystal structure of Mycobacterium tuberculosis KasA in complex with 6U5== | |||
<StructureSection load='5w2q' size='340' side='right'caption='[[5w2q]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5w2q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_str._Erdman_=_ATCC_35801 Mycobacterium tuberculosis str. Erdman = ATCC 35801]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W2Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W2Q 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6U5:~{N}-(1-METHYLINDAZOL-6-YL)BUTANE-1-SULFONAMIDE'>6U5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TCE:3,3,3-PHOSPHANETRIYLTRIPROPANOIC+ACID'>TCE</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=5w2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2q OCA], [https://pdbe.org/5w2q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w2q RCSB], [https://www.ebi.ac.uk/pdbsum/5w2q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2q ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KASA_MYCTU KASA_MYCTU] Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12023885, PubMed:12464486, PubMed:16873379, PubMed:22017312, PubMed:24108128). Involved in the initial extension of the mycolate chain and forms monounsaturated fatty acids that averaged 40 carbons in length (PubMed:12464486).<ref>PMID:11600501</ref> <ref>PMID:12023885</ref> <ref>PMID:12464486</ref> <ref>PMID:16873379</ref> <ref>PMID:22017312</ref> <ref>PMID:24108128</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report GSK3011724A (DG167) as a binary inhibitor of beta-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-A resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA-a key component for biosynthesis of the mycolic acid layer of the bacterium's cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars. | |||
Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA.,Kumar P, Capodagli GC, Awasthi D, Shrestha R, Maharaja K, Sukheja P, Li SG, Inoyama D, Zimmerman M, Ho Liang HP, Sarathy J, Mina M, Rasic G, Russo R, Perryman AL, Richmann T, Gupta A, Singleton E, Verma S, Husain S, Soteropoulos P, Wang Z, Morris R, Porter G, Agnihotri G, Salgame P, Ekins S, Rhee KY, Connell N, Dartois V, Neiditch MB, Freundlich JS, Alland D MBio. 2018 Dec 18;9(6). pii: mBio.02101-17. doi: 10.1128/mBio.02101-17. PMID:30563908<ref>PMID:30563908</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5w2q" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Acyl carrier protein synthase 3D structures|Acyl carrier protein synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis str. Erdman = ATCC 35801]] | |||
[[Category: Capodagli GC]] | |||
[[Category: Neiditch MB]] | |||