5dri: Difference between revisions
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==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid inhibitor== | ==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid inhibitor== | ||
<StructureSection load='5dri' size='340' side='right' caption='[[5dri]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='5dri' size='340' side='right'caption='[[5dri]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5dri]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DRI OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5dri]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DRI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DRI FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5EQ:(2Z)-2-HYDROXY-4-(1H-INDOL-5-YL)-4-OXOBUT-2-ENOIC+ACID'>5EQ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5EQ:(2Z)-2-HYDROXY-4-(1H-INDOL-5-YL)-4-OXOBUT-2-ENOIC+ACID'>5EQ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5drc|5drc]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5drc|5drc]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Malate_synthase Malate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.9 2.3.3.9] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Malate_synthase Malate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.9 2.3.3.9] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5dri FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dri OCA], [http://pdbe.org/5dri PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dri RCSB], [http://www.ebi.ac.uk/pdbsum/5dri PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dri ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5dri" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5dri" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Malate synthase 3D structures|Malate synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Malate synthase]] | [[Category: Malate synthase]] | ||
[[Category: Huang, H L]] | [[Category: Huang, H L]] | ||
Revision as of 11:03, 15 April 2020
Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid inhibitorCrystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid inhibitor
Structural highlights
Publication Abstract from PubMedFragment screening and high-throughput screening are complementary approaches that go hand in hand with structural biology to explore the binding capabilities of an active site and to provide diversity for inhibitor design. We used fragment-based approaches on malate synthase (GlcB) from Mycobacterium tuberculosis and discovered several novel binding chemotypes. In addition, the crystal structures of GlcB in complex with these fragments indicated conformational changes in the active site hypothesized to represent states the enzyme assumes in the substrate-product exchange during catalysis. Additional structures of the late product formation stage (in complex with malate) and of the apo form of GlcB supported that hypothesis. Comparative analysis of GlcB structures in complex with 18 fragments allowed us to characterize the preferred chemotypes and their modes of binding. The fragment structures showed a hydrogen bond to the backbone carbonyl of Met631, we successfully incorporated fragment moiety into an existing phenyl-diketo acid (PDKA) inhibitor to take advantage of this interaction. The result was 100-fold more potent than the parent PDKA indole-containing inhibitor with an IC 50 value of 20 nM. Mycobacterium tuberculosis Malate Synthase Structures with Fragments Reveal a Portal for Substrate/Product Exchange.,Huang HL, Krieger IV, Parai MK, Gawandi VB, Sacchettini JC J Biol Chem. 2016 Oct 13. pii: jbc.M116.750877. PMID:27738104[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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