5w2s: Difference between revisions
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<StructureSection load='5w2s' size='340' side='right' caption='[[5w2s]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5w2s' size='340' side='right' caption='[[5w2s]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5w2s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W2S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W2S FirstGlance]. <br> | <table><tr><td colspan='2'>[[5w2s]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycte Mycte]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W2S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W2S FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=KMG:N-(3-methyl-2H-indazol-5-yl)butane-1-sulfonamide'>KMG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=KMG:N-(3-methyl-2H-indazol-5-yl)butane-1-sulfonamide'>KMG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c72|4c72]], [[4c6w|4c6w]], [[4c70|4c70]], [[4c71|4c71]], [[4c73|4c73]], [[4c6z|4c6z]], [[2wge|2wge]], [[4c6x|4c6x]], [[2wgg|2wgg]], [[2wgd|2wgd]], [[5ld8|5ld8]], [[2wgf|2wgf]], [[4c6u|4c6u]], [[4c6v|4c6v]], [[5w2p|5w2p]], [[5w2o|5w2o]], [[5w2q|5w2q]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c72|4c72]], [[4c6w|4c6w]], [[4c70|4c70]], [[4c71|4c71]], [[4c73|4c73]], [[4c6z|4c6z]], [[2wge|2wge]], [[4c6x|4c6x]], [[2wgg|2wgg]], [[2wgd|2wgd]], [[5ld8|5ld8]], [[2wgf|2wgf]], [[4c6u|4c6u]], [[4c6v|4c6v]], [[5w2p|5w2p]], [[5w2o|5w2o]], [[5w2q|5w2q]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">kasA, ERDMAN_2470 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=652616 MYCTE])</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='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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5w2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2s OCA], [http://pdbe.org/5w2s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w2s RCSB], [http://www.ebi.ac.uk/pdbsum/5w2s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2s ProSAT]</span></td></tr> | <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=5w2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2s OCA], [http://pdbe.org/5w2s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w2s RCSB], [http://www.ebi.ac.uk/pdbsum/5w2s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2s ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/FAB1_MYCTE FAB1_MYCTE]] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. | [[http://www.uniprot.org/uniprot/FAB1_MYCTE FAB1_MYCTE]] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. | ||
<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> | |||
</div> | |||
<div class="pdbe-citations 5w2s" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Mycte]] | |||
[[Category: Capodagli, G C]] | [[Category: Capodagli, G C]] | ||
[[Category: Neiditch, M B]] | [[Category: Neiditch, M B]] | ||
Revision as of 09:44, 9 January 2019
Crystal Structure of Mycobacterium Tuberculosis KasA in complex with KMGCrystal Structure of Mycobacterium Tuberculosis KasA in complex with KMG
Structural highlights
Function[FAB1_MYCTE] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Publication Abstract from PubMedWe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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