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==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-3-(1H-indol-3-yl)propanoic acid== | ==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-3-(1H-indol-3-yl)propanoic acid== | ||
<StructureSection load='5cak' size='340' side='right' caption='[[5cak]], [[Resolution|resolution]] 1.99Å' scene=''> | <StructureSection load='5cak' size='340' side='right'caption='[[5cak]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5cak]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CAK OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5cak]] is a 1 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=5CAK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CAK FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4Z9:(2R)-2-HYDROXY-3-(1H-INDOL-3-YL)PROPANOIC+ACID'>4Z9</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4Z9:(2R)-2-HYDROXY-3-(1H-INDOL-3-YL)PROPANOIC+ACID'>4Z9</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cak FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cak OCA], [https://pdbe.org/5cak PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cak RCSB], [https://www.ebi.ac.uk/pdbsum/5cak PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cak ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/MASZ_MYCTU MASZ_MYCTU] Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA (By similarity).[HAMAP-Rule:MF_00641] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Fragment 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<ref>PMID:27738104</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 5cak" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5cak" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Malate synthase 3D structures|Malate synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: | [[Category: Huang H-L]] | ||
[[Category: | [[Category: Sacchettini JC]] | ||
Latest revision as of 11:36, 27 September 2023
Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-3-(1H-indol-3-yl)propanoic acidCrystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-3-(1H-indol-3-yl)propanoic acid
Structural highlights
FunctionMASZ_MYCTU Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA (By similarity).[HAMAP-Rule:MF_00641] 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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