5k4z - Revision history

OCA at 07:24, 1 May 2024

OCA — Wed, 01 May 2024 07:24:55 GMT

←Older revision		Revision as of 07:24, 1 May 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/G7CNL4_MYCT3 G7CNL4_MYCT3] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964]		[https://www.uniprot.org/uniprot/G7CNL4_MYCT3 G7CNL4_MYCT3] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964]
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above MIC for 24 hours were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate dependent, effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.
-
-	Essential but not vulnerable: indazole sulfonamides targeting inosine monophosphate dehydrogenase as potential leads against Mycobacterium tuberculosis.,Park Y, Pacitto A, Bayliss T, Cleghorn LA, Wang Z, Hartman T, Arora K, Ioerger TR, Sacchettini J, Rizzi M, Donini S, Blundell TL, Ascher DB, Rhee KY, Breda A, Zhou N, Dartois V, Jonnala SR, Via LE, Mizrahi V, Epemolu O, Stojanovski L, Simeons FR, Osuna-Cabello M, Ellis L, MacKenzie CJ, Smith AR, Davis SH, Murugesan D, Buchanan KI, Turner PA, Huggett M, Zuccotto F, Rebollo-Lopez MJ, Lafuente-Monasterio MJ, Sanz O, Santos Diaz G, Lelievre J, Ballell L, Selenski C, Axtman M, Ghidelli-Disse S, Pflaumer H, Boesche M, Drewes G, Freiberg G, Kurnick MD, Srikumaran M, Kempf DJ, Green SR, Ray PC, Read KD, Wyatt PG, Barry Rd CE, Boshoff HI ACS Infect Dis. 2016 Oct 5. PMID:27704782<ref>PMID:27704782</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5k4z" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Inosine monophosphate dehydrogenase 3D structures\|Inosine monophosphate dehydrogenase 3D structures]]		*[[Inosine monophosphate dehydrogenase 3D structures\|Inosine monophosphate dehydrogenase 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 10:39, 27 September 2023

OCA — Wed, 27 Sep 2023 10:39:44 GMT

←Older revision		Revision as of 10:39, 27 September 2023
Line 3:		Line 3:
	<StructureSection load='5k4z' size='340' side='right'caption='[[5k4z]], [[Resolution\|resolution]] 1.64Å' scene=''>		<StructureSection load='5k4z' size='340' side='right'caption='[[5k4z]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5k4z]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Atcc_19527 Atcc 19527~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K4Z OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5K4Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5k4z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_thermoresistibile Mycolicibacterium thermoresistibile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K4Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Q8:~{N}-(4-FLUOROPHENYL)-4-(2~{H}-INDAZOL-6-YLSULFAMOYL)-3,5-DIMETHYL-1~{H}-PYRROLE-2-CARBOXAMIDE'>6Q8</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</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]] 1.64Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RMCT_0580 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1797 ATCC 19527])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Q8:~{N}-(4-FLUOROPHENYL)-4-(2~{H}-INDAZOL-6-YLSULFAMOYL)-3,5-DIMETHYL-1~{H}-PYRROLE-2-CARBOXAMIDE'>6Q8</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5k4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k4z OCA], [~~http~~://pdbe.org/5k4z PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5k4z RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5k4z PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5k4z 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=5k4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k4z OCA], [https://pdbe.org/5k4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k4z RCSB], [https://www.ebi.ac.uk/pdbsum/5k4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k4z ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/~~A0A100XBM0_MYCTH A0A100XBM0_MYCTH]~~] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964]	+	[https://www.uniprot.org/uniprot/G7CNL4_MYCT3 G7CNL4_MYCT3] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Atcc 19527]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Ascher, D B~~]]	+	[[Category: Mycolicibacterium thermoresistibile]]
-	[[Category: ~~Blundell, T L~~]]	+	[[Category: Ascher DB]]
-	[[Category: ~~Pacitto, A~~]]	+	[[Category: Blundell TL]]
-	[[Category: ~~Guab2]]~~	+	[[Category: Pacitto A]]
-	~~[[Category: Impdh]]~~	+
-	~~[[Category: Inhibitor-complex]]~~	+
-	~~[[Category: Oxidoreductase~~]]	+

OCA at 09:19, 25 June 2020

OCA — Thu, 25 Jun 2020 09:19:22 GMT

←Older revision		Revision as of 09:19, 25 June 2020
Line 1:		Line 1:

	==M. thermoresistible IMPDH in complex with IMP and Compound 6==		==M. thermoresistible IMPDH in complex with IMP and Compound 6==
-	<StructureSection load='5k4z' size='340' side='right' caption='[[5k4z]], [[Resolution\|resolution]] 1.64Å' scene=''>	+	<StructureSection load='5k4z' size='340' side='right'caption='[[5k4z]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5k4z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K4Z OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5K4Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5k4z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_19527 Atcc 19527]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K4Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5K4Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Q8:~{N}-(4-FLUOROPHENYL)-4-(2~{H}-INDAZOL-6-YLSULFAMOYL)-3,5-DIMETHYL-1~{H}-PYRROLE-2-CARBOXAMIDE'>6Q8</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Q8:~{N}-(4-FLUOROPHENYL)-4-(2~{H}-INDAZOL-6-YLSULFAMOYL)-3,5-DIMETHYL-1~{H}-PYRROLE-2-CARBOXAMIDE'>6Q8</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></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=5k4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k4z OCA], [http://pdbe.org/5k4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k4z RCSB], [http://www.ebi.ac.uk/pdbsum/5k4z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k4z ProSAT]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RMCT_0580 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1797 ATCC 19527])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5k4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k4z OCA], [http://pdbe.org/5k4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k4z RCSB], [http://www.ebi.ac.uk/pdbsum/5k4z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k4z ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5k4z" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5k4z" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Inosine monophosphate dehydrogenase 3D structures\|Inosine monophosphate dehydrogenase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Atcc 19527]]
		+	[[Category: Large Structures]]
	[[Category: Ascher, D B]]		[[Category: Ascher, D B]]
	[[Category: Blundell, T L]]		[[Category: Blundell, T L]]

OCA at 17:18, 19 October 2016

OCA — Wed, 19 Oct 2016 17:18:19 GMT

←Older revision		Revision as of 17:18, 19 October 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5k4z is ~~ON HOLD until Paper~~ Publication	+	==M. thermoresistible IMPDH in complex with IMP and Compound 6==
		+	<StructureSection load='5k4z' size='340' side='right' caption='[[5k4z]], [[Resolution\|resolution]] 1.64Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5k4z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K4Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K4Z FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Q8:~{N}-(4-FLUOROPHENYL)-4-(2~{H}-INDAZOL-6-YLSULFAMOYL)-3,5-DIMETHYL-1~{H}-PYRROLE-2-CARBOXAMIDE'>6Q8</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></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=5k4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k4z OCA], [http://pdbe.org/5k4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k4z RCSB], [http://www.ebi.ac.uk/pdbsum/5k4z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k4z ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/A0A100XBM0_MYCTH A0A100XBM0_MYCTH]] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above MIC for 24 hours were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate dependent, effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

-	~~Authors~~: ~~Pacitto~~, A., Ascher, D~~.B.~~, ~~Blundell~~, T.L.	+	Essential but not vulnerable: indazole sulfonamides targeting inosine monophosphate dehydrogenase as potential leads against Mycobacterium tuberculosis.,Park Y, Pacitto A, Bayliss T, Cleghorn LA, Wang Z, Hartman T, Arora K, Ioerger TR, Sacchettini J, Rizzi M, Donini S, Blundell TL, Ascher DB, Rhee KY, Breda A, Zhou N, Dartois V, Jonnala SR, Via LE, Mizrahi V, Epemolu O, Stojanovski L, Simeons FR, Osuna-Cabello M, Ellis L, MacKenzie CJ, Smith AR, Davis SH, Murugesan D, Buchanan KI, Turner PA, Huggett M, Zuccotto F, Rebollo-Lopez MJ, Lafuente-Monasterio MJ, Sanz O, Santos Diaz G, Lelievre J, Ballell L, Selenski C, Axtman M, Ghidelli-Disse S, Pflaumer H, Boesche M, Drewes G, Freiberg G, Kurnick MD, Srikumaran M, Kempf DJ, Green SR, Ray PC, Read KD, Wyatt PG, Barry Rd CE, Boshoff HI ACS Infect Dis. 2016 Oct 5. PMID:27704782<ref>PMID:27704782</ref>

-	~~Description: M~~. ~~thermoresistible IMPDH in complex with IMP and Compound 6~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5k4z" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Ascher, D B]]
		+	[[Category: Blundell, T L]]
	[[Category: Pacitto, A]]		[[Category: Pacitto, A]]
-	[[Category: ~~Blundell, T.L~~]]	+	[[Category: Guab2]]
-	[[Category: ~~Ascher, D.B~~]]	+	[[Category: Impdh]]
		+	[[Category: Inhibitor-complex]]
		+	[[Category: Oxidoreductase]]

OCA at 13:26, 20 June 2016

OCA — Mon, 20 Jun 2016 13:26:20 GMT

←Older revision		Revision as of 13:26, 20 June 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5k4z is ON HOLD	+	The entry 5k4z is ON HOLD until Paper Publication

	Authors: Pacitto, A., Ascher, D.B., Blundell, T.L.		Authors: Pacitto, A., Ascher, D.B., Blundell, T.L.

OCA: Protected "5k4z" [edit=sysop:move=sysop]

OCA — Wed, 01 Jun 2016 14:19:57 GMT

Protected "5k4z" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:19, 1 June 2016

OCA: New page: '''Unreleased structure''' The entry 5k4z is ON HOLD Authors: Pacitto, A., Ascher, D.B., Blundell, T.L. Description: M. thermoresistible IMPDH in complex with IMP and Compound 6 [[Cate...

OCA — Wed, 01 Jun 2016 14:19:56 GMT

New page: '''Unreleased structure''' The entry 5k4z is ON HOLD Authors: Pacitto, A., Ascher, D.B., Blundell, T.L. Description: M. thermoresistible IMPDH in complex with IMP and Compound 6 [[Cate...

New page

'''Unreleased structure'''

The entry 5k4z is ON HOLD

Authors: Pacitto, A., Ascher, D.B., Blundell, T.L.

Description: M. thermoresistible IMPDH in complex with IMP and Compound 6
[[Category: Unreleased Structures]]
[[Category: Pacitto, A]]
[[Category: Blundell, T.L]]
[[Category: Ascher, D.B]]