5ld8

From Proteopedia

(Difference between revisions)

Current revision

GSK3011724A cocrystallised with Mycobacterium tuberculosis H37Rv KasA

Structural highlights

5ld8 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.13Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis beta-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related beta-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

Identification of KasA as the cellular target of an anti-tubercular scaffold.,Abrahams KA, Chung CW, Ghidelli-Disse S, Rullas J, Rebollo-Lopez MJ, Gurcha SS, Cox JA, Mendoza A, Jimenez-Navarro E, Martinez-Martinez MS, Neu M, Shillings A, Homes P, Argyrou A, Casanueva R, Loman NJ, Moynihan PJ, Lelievre J, Selenski C, Axtman M, Kremer L, Bantscheff M, Angulo-Barturen I, Izquierdo MC, Cammack NC, Drewes G, Ballell L, Barros D, Besra GS, Bates RH Nat Commun. 2016 Sep 1;7:12581. doi: 10.1038/ncomms12581. PMID:27581223^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schaeffer ML, Agnihotri G, Volker C, Kallender H, Brennan PJ, Lonsdale JT. Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. J Biol Chem. 2001 Dec 14;276(50):47029-37. PMID:11600501 doi:10.1074/jbc.M108903200
↑ Kremer L, Dover LG, Carrère S, Nampoothiri KM, Lesjean S, Brown AK, Brennan PJ, Minnikin DE, Locht C, Besra GS. Mycolic acid biosynthesis and enzymic characterization of the beta-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochem J. 2002 Jun 1;364(Pt 2):423-30. PMID:12023885 doi:10.1042/BJ20011628
↑ Slayden RA, Barry CE 3rd. The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2002;82(4-5):149-60. PMID:12464486 doi:10.1054/tube.2002.0333
↑ Molle V, Brown AK, Besra GS, Cozzone AJ, Kremer L. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem. 2006 Oct 6;281(40):30094-103. PMID:16873379 doi:10.1074/jbc.M601691200
↑ Borgaro JG, Chang A, Machutta CA, Zhang X, Tonge PJ. Substrate recognition by β-ketoacyl-ACP synthases. Biochemistry. 2011 Dec 13;50(49):10678-86. PMID:22017312 doi:10.1021/bi201199x
↑ Schiebel J, Kapilashrami K, Fekete A, Bommineni GR, Schaefer CM, Mueller MJ, Tonge PJ, Kisker C. Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis. J Biol Chem. 2013 Oct 9. PMID:24108128 doi:http://dx.doi.org/10.1074/jbc.M113.511436
↑ Abrahams KA, Chung CW, Ghidelli-Disse S, Rullas J, Rebollo-Lopez MJ, Gurcha SS, Cox JA, Mendoza A, Jimenez-Navarro E, Martinez-Martinez MS, Neu M, Shillings A, Homes P, Argyrou A, Casanueva R, Loman NJ, Moynihan PJ, Lelievre J, Selenski C, Axtman M, Kremer L, Bantscheff M, Angulo-Barturen I, Izquierdo MC, Cammack NC, Drewes G, Ballell L, Barros D, Besra GS, Bates RH. Identification of KasA as the cellular target of an anti-tubercular scaffold. Nat Commun. 2016 Sep 1;7:12581. doi: 10.1038/ncomms12581. PMID:27581223 doi:http://dx.doi.org/10.1038/ncomms12581

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ld8"

Categories: Large Structures | Mycobacterium tuberculosis H37Rv | Chung CW | Neu M

@@ Line 3: / Line 3: @@
 <StructureSection load='5ld8' size='340' side='right'caption='[[5ld8]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ld8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LD8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LD8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ld8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LD8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LD8 FirstGlance]. <br>
-</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 2.13&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">kasA, Rv2245, MTCY427.26 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-ketoacyl-[acyl-carrier-protein]_synthase_I Beta-ketoacyl-[acyl-carrier-protein] synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] </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=5ld8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ld8 OCA], [https://pdbe.org/5ld8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ld8 RCSB], [https://www.ebi.ac.uk/pdbsum/5ld8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ld8 ProSAT]</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=5ld8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ld8 OCA], [http://pdbe.org/5ld8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ld8 RCSB], [http://www.ebi.ac.uk/pdbsum/5ld8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ld8 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/FAB1_MYCTU FAB1_MYCTU]] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity).
+[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 ==
@@ Line 28: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myctu]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Chung, C W]]
+[[Category: Chung CW]]
-[[Category: Neu, M]]
+[[Category: Neu M]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Kasa]]
-[[Category: Mycobacterium tuberculosis]]
-[[Category: Transferase]]

5ld8

From Proteopedia

Current revision

GSK3011724A cocrystallised with Mycobacterium tuberculosis H37Rv KasA

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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