6jvr - Revision history

OCA at 10:40, 27 March 2024

OCA — Wed, 27 Mar 2024 10:40:08 GMT

←Older revision		Revision as of 10:40, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6jvr' size='340' side='right'caption='[[6jvr]], [[Resolution\|resolution]] 2.29Å' scene=''>		<StructureSection load='6jvr' size='340' side='right'caption='[[6jvr]], [[Resolution\|resolution]] 2.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6jvr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JVR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jvr]] is a 2 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=6JVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JVR FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=CJU:N4-methyl-6-piperidin-1-yl-pyrimidine~~-2~~,4-diamine'>CJU</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]] 2.295Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat">~~NUDT1~~, ~~MTH1 ([https:~~/~~/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=CJU:N4-methyl-6-piperidin-1-yl-pyrimidine-2,4-diamine'>CJU</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=6jvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jvr OCA], [https://pdbe.org/6jvr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jvr RCSB], [https://www.ebi.ac.uk/pdbsum/6jvr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jvr 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=6jvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jvr OCA], [https://pdbe.org/6jvr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jvr RCSB], [https://www.ebi.ac.uk/pdbsum/6jvr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jvr ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[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>	+	[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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.	+
-		+
-	Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.,Peng C, Li YH, Yu CW, Cheng ZH, Liu JR, Hsu JL, Hsin LW, Huang CT, Juan HF, Chern JW, Cheng YS Bioorg Chem. 2021 May;110:104813. doi: 10.1016/j.bioorg.2021.104813. Epub 2021, Mar 10. PMID:33774493<ref>PMID:33774493</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6jvr" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 26:		Line 17:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cheng~~, Y S~~]]	+	[[Category: Cheng YS]]
-	[[Category: Li~~, Y H~~]]	+	[[Category: Li YH]]
-	[[Category: Peng, C]]	+	[[Category: Peng C]]
-	~~[[Category: 8-oxo-dgtp]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Inhibitor development]]~~	+
-	~~[[Category: Mth1]]~~	+
-	~~[[Category: Oxidative dna damage~~]]	+

OCA at 09:33, 12 May 2021

OCA — Wed, 12 May 2021 09:33:32 GMT

←Older revision		Revision as of 09:33, 12 May 2021
Line 1:		Line 1:

	==Crystal structure of human MTH1 in complex with compound MI1026==		==Crystal structure of human MTH1 in complex with compound MI1026==
-	<StructureSection load='6jvr' size='340' side='right'caption='[[6jvr]]' scene=''>	+	<StructureSection load='6jvr' size='340' side='right'caption='[[6jvr]], [[Resolution\|resolution]] 2.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JVR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6JVR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jvr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JVR FirstGlance]. <br>
-	</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=6jvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jvr OCA], [~~http~~://pdbe.org/6jvr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6jvr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6jvr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6jvr ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJU:N4-methyl-6-piperidin-1-yl-pyrimidine-2,4-diamine'>CJU</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NUDT1, MTH1 ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6jvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jvr OCA], [https://pdbe.org/6jvr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jvr RCSB], [https://www.ebi.ac.uk/pdbsum/6jvr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jvr ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[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;">
		+	== Publication Abstract from PubMed ==
		+	MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.
		+
		+	Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.,Peng C, Li YH, Yu CW, Cheng ZH, Liu JR, Hsu JL, Hsin LW, Huang CT, Juan HF, Chern JW, Cheng YS Bioorg Chem. 2021 May;110:104813. doi: 10.1016/j.bioorg.2021.104813. Epub 2021, Mar 10. PMID:33774493<ref>PMID:33774493</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6jvr" 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/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cheng YS]]	+	[[Category: Cheng, Y S]]
-	[[Category: Li YH]]	+	[[Category: Li, Y H]]
-	[[Category: Peng C]]	+	[[Category: Peng, C]]
		+	[[Category: 8-oxo-dgtp]]
		+	[[Category: Hydrolase]]
		+	[[Category: Inhibitor development]]
		+	[[Category: Mth1]]
		+	[[Category: Oxidative dna damage]]

OCA at 20:30, 28 October 2020

OCA — Wed, 28 Oct 2020 20:30:50 GMT

←Older revision		Revision as of 20:30, 28 October 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6jvr is ~~ON HOLD until Oct 22 2021~~	+	==Crystal structure of human MTH1 in complex with compound MI1026==
-		+	<StructureSection load='6jvr' size='340' side='right'caption='[[6jvr]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JVR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JVR FirstGlance]. <br>
-	~~Description~~:	+	</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=6jvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jvr OCA], [http://pdbe.org/6jvr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jvr RCSB], [http://www.ebi.ac.uk/pdbsum/6jvr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jvr ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Cheng YS]]
		+	[[Category: Li YH]]
		+	[[Category: Peng C]]

OCA at 05:24, 8 April 2020

OCA — Wed, 08 Apr 2020 05:24:00 GMT

←Older revision		Revision as of 05:24, 8 April 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6jvr is ON HOLD until ~~Paper Publication~~	+	The entry 6jvr is ON HOLD until Oct 22 2021

	Authors:		Authors:

OCA at 04:20, 29 May 2019

OCA — Wed, 29 May 2019 04:20:50 GMT

←Older revision		Revision as of 04:20, 29 May 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6jvr is ON HOLD	+	The entry 6jvr is ON HOLD until Paper Publication

	Authors:		Authors:

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

OCA — Wed, 24 Apr 2019 04:48:51 GMT

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

←Older revision

Revision as of 04:48, 24 April 2019

OCA: New page: '''Unreleased structure''' The entry 6jvr is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 24 Apr 2019 04:48:49 GMT

New page: '''Unreleased structure''' The entry 6jvr is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6jvr is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]