6eq4 - Revision history

OCA at 12:20, 9 May 2024

OCA — Thu, 09 May 2024 12:20:55 GMT

←Older revision		Revision as of 12:20, 9 May 2024
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	<StructureSection load='6eq4' size='340' side='right'caption='[[6eq4]], [[Resolution\|resolution]] 1.40Å' scene=''>		<StructureSection load='6eq4' size='340' side='right'caption='[[6eq4]], [[Resolution\|resolution]] 1.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6eq4]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EQ4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6EQ4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6eq4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EQ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EQ4 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BSW:4-(3-fluoranylpyridin-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine'>BSW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.4Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NUDT1, MTH1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BSW:4-(3-fluoranylpyridin-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine'>BSW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6eq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eq4 OCA], [~~http~~://pdbe.org/6eq4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6eq4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6eq4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6eq4 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=6eq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eq4 OCA], [https://pdbe.org/6eq4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eq4 RCSB], [https://www.ebi.ac.uk/pdbsum/6eq4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eq4 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>	+	[https://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 6eq4" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6eq4" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures\|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Caflisch, A]]	+	[[Category: Caflisch A]]
-	[[Category: Sledz, P]]	+	[[Category: Sledz P]]
-	[[Category: Wiedmer, L]]	+	[[Category: Wiedmer L]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Dna repair]]~~	+
-	~~[[Category: Fragment]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Inhibitor~~]]	+

OCA at 07:30, 23 May 2019

OCA — Thu, 23 May 2019 07:30:19 GMT

←Older revision		Revision as of 07:30, 23 May 2019
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>		[[http://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The DNA-repair enzyme MutT homolog 1 (MTH1) is a potential target for a broad range of tumors. Its substrate binding site features a non-catalytical pair of aspartic acids which resembles the catalytic dyad of aspartic proteases. We hypothesized that inhibitors of the latter might be re-targeted for MTH1 despite the two enzyme classes having different substrates and catalyze different reactions. We selected from the crystal structures of holo aspartic proteases a library of nearly 350 inhibitors for in silico screening. Three fragment hits were identified by docking and scoring according to a force field-based energy with continuum dielectric solvation. These fragments showed good ligand efficiency in a colorimetric assay (MW <300 Da and IC50<50muM). Molecular dynamics simulations were carried out for determining the most favorable interaction patterns. On the basis of the simulation results we evaluated in vitro seven commercially available compounds, two of which showed submicromolar potency for MTH1. To obtain definitive evidence of the predicted binding modes we solved the crystal structures of five of the 10 inhibitors predicted in silico. The final step of hit optimization was guided by protein crystallography and involved the synthesis of a single compound, the lead 11, which shows nanomolar affinity for MTH1 in two orthogonal binding assays, and selectivity higher than 2000-fold against its original target (BACE1). The high rate of fragment-hit identification and the fast optimization suggest that ligand retargeting by binding site analogy is an efficient strategy for drug design.
		+
		+	Ligand retargeting by binding site analogy.,Wiedmer L, Scharer C, Spiliotopoulos D, Hurzeler M, Sledz P, Caflisch A Eur J Med Chem. 2019 Apr 25;175:107-113. doi: 10.1016/j.ejmech.2019.04.037. PMID:31077996<ref>PMID:31077996</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6eq4" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 08:11, 21 May 2019

OCA — Tue, 21 May 2019 08:11:27 GMT

←Older revision		Revision as of 08:11, 21 May 2019
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	==MTH1 in complex with fragment 8==		==MTH1 in complex with fragment 8==
-	<StructureSection load='6eq4' size='340' side='right' caption='[[6eq4]], [[Resolution\|resolution]] 1.40Å' scene=''>	+	<StructureSection load='6eq4' size='340' side='right'caption='[[6eq4]], [[Resolution\|resolution]] 1.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6eq4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EQ4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6eq4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EQ4 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BSW:4-(3-fluoranylpyridin-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine'>BSW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BSW:4-(3-fluoranylpyridin-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine'>BSW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NUDT1, MTH1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6eq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eq4 OCA], [http://pdbe.org/6eq4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eq4 RCSB], [http://www.ebi.ac.uk/pdbsum/6eq4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eq4 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=6eq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eq4 OCA], [http://pdbe.org/6eq4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eq4 RCSB], [http://www.ebi.ac.uk/pdbsum/6eq4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eq4 ProSAT]</span></td></tr>
	</table>		</table>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Caflisch, A]]		[[Category: Caflisch, A]]
	[[Category: Sledz, P]]		[[Category: Sledz, P]]

OCA at 06:53, 31 October 2018

OCA — Wed, 31 Oct 2018 06:53:39 GMT

←Older revision		Revision as of 06:53, 31 October 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6eq4 is ~~ON HOLD until Paper Publication~~	+	==MTH1 in complex with fragment 8==
-		+	<StructureSection load='6eq4' size='340' side='right' caption='[[6eq4]], [[Resolution\|resolution]] 1.40Å' scene=''>
-	~~Authors~~: ~~Wiedmer~~, L., ~~Sledz~~, P., ~~Caflisch~~, A.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6eq4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EQ4 FirstGlance]. <br>
-	~~Description: MTH1 in complex with fragment 8~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BSW:4-(3-fluoranylpyridin-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine'>BSW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	<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=6eq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eq4 OCA], [http://pdbe.org/6eq4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eq4 RCSB], [http://www.ebi.ac.uk/pdbsum/6eq4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eq4 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Caflisch, A]]		[[Category: Caflisch, A]]
	[[Category: Sledz, P]]		[[Category: Sledz, P]]
	[[Category: Wiedmer, L]]		[[Category: Wiedmer, L]]
		+	[[Category: Complex]]
		+	[[Category: Dna repair]]
		+	[[Category: Fragment]]
		+	[[Category: Hydrolase]]
		+	[[Category: Inhibitor]]

OCA: Protected "6eq4" [edit=sysop:move=sysop]

OCA — Wed, 08 Nov 2017 06:40:12 GMT

Protected "6eq4" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:40, 8 November 2017

OCA: New page: '''Unreleased structure''' The entry 6eq4 is ON HOLD until Paper Publication Authors: Wiedmer, L., Sledz, P., Caflisch, A. Description: MTH1 in complex with fragment 8 [[Category: Unre...

OCA — Wed, 08 Nov 2017 06:40:11 GMT

New page: '''Unreleased structure''' The entry 6eq4 is ON HOLD until Paper Publication Authors: Wiedmer, L., Sledz, P., Caflisch, A. Description: MTH1 in complex with fragment 8 [[Category: Unre...

New page

'''Unreleased structure'''

The entry 6eq4 is ON HOLD until Paper Publication

Authors: Wiedmer, L., Sledz, P., Caflisch, A.

Description: MTH1 in complex with fragment 8
[[Category: Unreleased Structures]]
[[Category: Caflisch, A]]
[[Category: Sledz, P]]
[[Category: Wiedmer, L]]