6p9k: Difference between revisions

Latest revision as of 07:25, 11 October 2023

Crystal structure of Mycobacterium tuberculosis KasA in complex with O6G

Structural highlights

6p9k is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.703Å
Ligands:	GOL, IPA, NA, O6G
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

Published Mycobacterium tuberculosis beta-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.,Inoyama D, Awasthi D, Capodagli GC, Tsotetsi K, Sukheja P, Zimmerman M, Li SG, Jadhav R, Russo R, Wang X, Grady C, Richmann T, Shrestha R, Li L, Ahn YM, Ho Liang HP, Mina M, Park S, Perlin DS, Connell N, Dartois V, Alland D, Neiditch MB, Kumar P, Freundlich JS Cell Chem Biol. 2020 Mar 19. pii: S2451-9456(20)30071-4. doi:, 10.1016/j.chembiol.2020.02.007. PMID:32197094^[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:https://dx.doi.org/10.1074/jbc.M113.511436
↑ Inoyama D, Awasthi D, Capodagli GC, Tsotetsi K, Sukheja P, Zimmerman M, Li SG, Jadhav R, Russo R, Wang X, Grady C, Richmann T, Shrestha R, Li L, Ahn YM, Ho Liang HP, Mina M, Park S, Perlin DS, Connell N, Dartois V, Alland D, Neiditch MB, Kumar P, Freundlich JS. A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA. Cell Chem Biol. 2020 Mar 19. pii: S2451-9456(20)30071-4. doi:, 10.1016/j.chembiol.2020.02.007. PMID:32197094 doi:https://dx.doi.org/10.1016/j.chembiol.2020.02.007

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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:https://dx.doi.org/10.1074/jbc.M113.511436

[7] Inoyama D, Awasthi D, Capodagli GC, Tsotetsi K, Sukheja P, Zimmerman M, Li SG, Jadhav R, Russo R, Wang X, Grady C, Richmann T, Shrestha R, Li L, Ahn YM, Ho Liang HP, Mina M, Park S, Perlin DS, Connell N, Dartois V, Alland D, Neiditch MB, Kumar P, Freundlich JS. A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA. Cell Chem Biol. 2020 Mar 19. pii: S2451-9456(20)30071-4. doi:, 10.1016/j.chembiol.2020.02.007. PMID:32197094 doi:https://dx.doi.org/10.1016/j.chembiol.2020.02.007

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[2]

[3]

[4]

[5]

[6]

[7]

@@ Line 3: / Line 3: @@
 <StructureSection load='6p9k' size='340' side='right'caption='[[6p9k]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6p9k]] is a 1 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=6P9K OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6P9K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6p9k]] is a 1 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=6P9K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P9K FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=O6G:N-(2-cyano-3-methyl-1H-indol-5-yl)butane-1-sulfonamide'>O6G</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]] 1.703&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5w2o|5w2o]], [[5w2p|5w2p]], [[5w2q|5w2q]], [[5w2s|5w2s]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=O6G:N-(2-cyano-3-methyl-1H-indol-5-yl)butane-1-sulfonamide'>O6G</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">kasA_2, kasA, kasA_1, ERS007663_00367, ERS007672_01613, ERS007679_01974, ERS007681_02066, ERS007688_01478, ERS007703_02203, ERS007722_03184, ERS007741_02349, ERS023446_01403, ERS024276_01522, ERS027644_00736, ERS027646_00897, ERS027651_00106, ERS027652_01351, ERS027656_00221, ERS027659_01260, ERS027666_02494, ERS031537_00603, ERS124361_03146, SAMEA2683035_01249 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=6p9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p9k OCA], [https://pdbe.org/6p9k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p9k RCSB], [https://www.ebi.ac.uk/pdbsum/6p9k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p9k ProSAT]</span></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'>[http://proteopedia.org/fgij/fg.htm?mol=6p9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p9k OCA], [http://pdbe.org/6p9k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p9k RCSB], [http://www.ebi.ac.uk/pdbsum/6p9k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p9k 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 ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6p9k" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Acyl carrier protein synthase 3D structures|Acyl carrier protein synthase 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Capodagli, G C]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Neiditch, M B]]
+[[Category: Capodagli GC]]
-[[Category: Beta ketoacyl synthase i]]
+[[Category: Neiditch MB]]
-[[Category: Fatty acid biosynthesis]]
-[[Category: Lipid synthesis]]
-[[Category: Transferase]]

6p9k: Difference between revisions

Latest revision as of 07:25, 11 October 2023

Crystal structure of Mycobacterium tuberculosis KasA in complex with O6G

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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