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==
-<StructureSection load='5dri' size='340' side='right' caption='[[5dri]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='5dri' size='340' side='right'caption='[[5dri]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DRI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5dri]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Ra Mycobacterium tuberculosis H37Ra]. 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 [https://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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5drc|5drc]]</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='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'>[https://proteopedia.org/fgij/fg.htm?mol=5dri FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dri OCA], [https://pdbe.org/5dri PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dri RCSB], [https://www.ebi.ac.uk/pdbsum/5dri PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dri 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=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>
+== 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;">
 == Publication Abstract from PubMed ==
-Establishment or maintenance of a persistent infection by Mycobacterium tuberculosis requires the glyoxylate pathway. This is a bypass of the tricarboxylic acid cycle in which isocitrate lyase and malate synthase (GlcB) catalyze the net incorporation of carbon during growth of microorganisms on acetate or fatty acids as the primary carbon source. The glcB gene from M. tuberculosis, which encodes malate synthase, was cloned, and GlcB was expressed in Escherichia coli. The influence of media conditions on expression in M. tuberculosis indicated that this enzyme is regulated differentially to isocitrate lyase. Purified GlcB had K(m) values of 57 and 30 microm for its substrates glyoxylate and acetyl coenzyme A, respectively, and was inhibited by bromopyruvate, oxalate, and phosphoenolpyruvate. The GlcB structure was solved to 2.1-A resolution in the presence of glyoxylate and magnesium. We also report the structure of GlcB in complex with the products of the reaction, coenzyme A and malate, solved to 2.7-A resolution. Coenzyme A binds in a bent conformation, and the details of its interactions are described, together with implications on the enzyme mechanism.
+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.
-Biochemical and structural studies of malate synthase from Mycobacterium tuberculosis.,Smith CV, Huang CC, Miczak A, Russell DG, Sacchettini JC, Honer zu Bentrup K J Biol Chem. 2003 Jan 17;278(3):1735-43. Epub 2002 Oct 21. PMID:12393860<ref>PMID:12393860</ref>
+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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 <div class="pdbe-citations 5dri" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Malate synthase 3D structures|Malate synthase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Malate synthase]]
+[[Category: Large Structures]]
-[[Category: Huang, H L]]
+[[Category: Mycobacterium tuberculosis H37Ra]]
-[[Category: Krieger, I V]]
+[[Category: Huang H-L]]
-[[Category: Sacchettini, J C]]
+[[Category: Krieger IV]]
-[[Category: Acetyltransferase]]
+[[Category: Sacchettini JC]]
-[[Category: Transferase]]