5cbb - Revision history

OCA at 08:36, 27 September 2023

2023-09-27T08:36:31Z

← Older revision		Revision as of 08:36, 27 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5cbb]] 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=5CBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CBB FirstGlance]. <br>		<table><tr><td colspan='2'>[[5cbb]] 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=5CBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CBB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</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]] 2.012Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</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'>[https://proteopedia.org/fgij/fg.htm?mol=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [https://pdbe.org/5cbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [https://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb ProSAT]</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=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [https://pdbe.org/5cbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [https://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb ProSAT]</span></td></tr>
	</table>		</table>

OCA at 11:55, 14 June 2023

2023-06-14T11:55:20Z

← Older revision		Revision as of 11:55, 14 June 2023
Line 1:		Line 1:

	==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 5-(3H-indol-3-ylidene)-2,5-dihydro-1H-pyrazole-3-carboxylate==		==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 5-(3H-indol-3-ylidene)-2,5-dihydro-1H-pyrazole-3-carboxylate==
	<StructureSection load='5cbb' size='340' side='right' caption='[[5cbb]], [[Resolution\|resolution]] 2.01Å' scene=''>		<StructureSection load='5cbb' size='340' side='right'caption='[[5cbb]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5cbb]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Myctu Myctu~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CBB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5CBB FirstGlance]. <br>		<table><tr><td colspan='2'>[[5cbb]] 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=5CBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CBB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</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=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">glcB, Rv1837c, MTCY1A11.06 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [https://pdbe.org/5cbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [https://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb 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/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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [~~http~~://pdbe.org/5cbb PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[~~[http~~://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]		[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 ==
Line 20:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 5cbb" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5cbb" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Malate synthase 3D structures\|Malate synthase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Malate synthase~~]]		[[Category: Large Structures]]
	[[Category: ~~Myctu~~]]		[[Category: Mycobacterium tuberculosis H37Rv]]
	[[Category: Huang, H L]]		[[Category: Huang H-L]]
	[[Category: Sacchettini~~, J C]]~~		[[Category: Sacchettini JC]]
	~~[[Category: Acetyltransferase]]~~
	~~[[Category: Complex]]~~
	~~[[Category: Fragment]]~~
	~~[[Category: Transferase~~]]

OCA at 12:26, 6 November 2017

2017-11-06T12:26:17Z

← Older revision		Revision as of 12:26, 6 November 2017
Line 3:		Line 3:
	<StructureSection load='5cbb' size='340' side='right' caption='[[5cbb]], [[Resolution\|resolution]] 2.01Å' scene=''>		<StructureSection load='5cbb' size='340' side='right' caption='[[5cbb]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5cbb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CBB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CBB FirstGlance]. <br>		<table><tr><td colspan='2'>[[5cbb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CBB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CBB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</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"><scene name='pdbligand=4ZF:(5E)-5-(3H-INDOL-3-YLIDENE)-2,5-DIHYDRO-1H-PYRAZOLE-3-CARBOXYLIC+ACID'>4ZF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">glcB, Rv1837c, MTCY1A11.06 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [http://pdbe.org/5cbb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [http://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb 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=5cbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbb OCA], [http://pdbe.org/5cbb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cbb RCSB], [http://www.ebi.ac.uk/pdbsum/5cbb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbb ProSAT]</span></td></tr>
Line 24:		Line 25:
	</StructureSection>		</StructureSection>
	[[Category: Malate synthase]]		[[Category: Malate synthase]]
			[[Category: Myctu]]
	[[Category: Huang, H L]]		[[Category: Huang, H L]]
	[[Category: Sacchettini, J C]]		[[Category: Sacchettini, J C]]

OCA at 11:05, 26 October 2016

2016-10-26T11:05:20Z

← Older revision		Revision as of 11:05, 26 October 2016
Line 12:		Line 12:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
	~~The glyoxylate shunt plays an important role in fatty acid metabolism~~ and ~~has been shown to be critical to survival of several pathogens involved~~ in ~~chronic infections. For Mycobacterium tuberculosis (Mtb), a strain~~ with ~~a defective glyoxylate shunt was previously shown~~ to ~~be unable~~ to ~~establish infection in a mouse model~~. We ~~report the development of phenyl~~-~~diketo acid (PDKA) inhibitors of~~ malate synthase (GlcB), ~~one~~ of ~~two glyoxylate shunt enzymes, using structure~~-~~based methods~~. ~~PDKA inhibitors were active against Mtb grown on acetate,~~ and ~~overexpression~~ of GlcB ~~ameliorated this inhibition~~. ~~Crystal structures of complexes~~ of GlcB with ~~PDKA inhibitors guided optimization~~ of ~~potency~~. ~~A selected~~ PDKA ~~compound demonstrated efficacy in a mouse model~~ of ~~tuberculosis~~. The ~~discovery of these~~ PDKA ~~derivatives provides chemical validation~~ of ~~GlcB as an attractive target for tuberculosis therapeutics~~.		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.

	~~Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M.~~ tuberculosis ~~malate synthase~~.,Krieger IV, ~~Freundlich JS, Gawandi VB, Roberts JP~~, Gawandi VB~~, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera JL, Ioerger TR~~, Sacchettini JC Chem ~~Biol~~. ~~2012 Dec 21;19(12):1556-67~~. ~~doi~~: ~~10.1016/j.chembiol.2012~~.09.~~018~~. PMID:~~23261599~~<ref>PMID:~~23261599~~</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®/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>

OCA at 15:49, 10 August 2016

2016-08-10T15:49:23Z

@@ Line 1: / Line 1: @@
-The entry 5cbb is ON HOLD  until Paper Publication
+==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 5-(3H-indol-3-ylidene)-2,5-dihydro-1H-pyrazole-3-carboxylate==
-Authors: Huang, H.-L., Sacchettini, J.C.
+Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.,Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera JL, Ioerger TR, Sacchettini JC Chem Biol. 2012 Dec 21;19(12):1556-67. doi: 10.1016/j.chembiol.2012.09.018. PMID:23261599<ref>PMID:23261599</ref>
-Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 5-(3H-indol-3-ylidene)-2,5-dihydro-1H-pyrazole-3-carboxylate
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Sacchettini, J.C]]
+<div class="pdbe-citations 5cbb" style="background-color:#fffaf0;"></div>
-[[Category: Huang, H.-L]]
+== References ==

OCA at 12:59, 2 December 2015

2015-12-02T12:59:00Z

← Older revision		Revision as of 12:59, 2 December 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 5cbb is ON HOLD		The entry 5cbb is ON HOLD until Paper Publication

	Authors: Huang, H.-L., Sacchettini, J.C.		Authors: Huang, H.-L., Sacchettini, J.C.

	Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 3-(4-~~fluorophenyl~~)-4-~~methyl~~-1H-~~pyrazol~~-5-~~amine~~		Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 5-(3H-indol-3-ylidene)-2,5-dihydro-1H-pyrazole-3-carboxylate
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Sacchettini, J.C]]		[[Category: Sacchettini, J.C]]
	[[Category: Huang, H.-L]]		[[Category: Huang, H.-L]]

OCA: Protected "5cbb" [edit=sysop:move=sysop]

2015-07-08T13:56:11Z

Protected "5cbb" [edit=sysop:move=sysop]

← Older revision	Revision as of 13:56, 8 July 2015
(No difference)

OCA: New page: '''Unreleased structure''' The entry 5cbb is ON HOLD Authors: Huang, H.-L., Sacchettini, J.C. Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex wi...

2015-07-08T13:56:10Z

New page: '''Unreleased structure''' The entry 5cbb is ON HOLD Authors: Huang, H.-L., Sacchettini, J.C. Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex wi...

New page

'''Unreleased structure'''

The entry 5cbb is ON HOLD

Authors: Huang, H.-L., Sacchettini, J.C.

Description: Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 3-(4-fluorophenyl)-4-methyl-1H-pyrazol-5-amine
[[Category: Unreleased Structures]]
[[Category: Sacchettini, J.C]]
[[Category: Huang, H.-L]]