6ili - Revision history

OCA at 10:33, 27 March 2024

OCA — Wed, 27 Mar 2024 10:33:44 GMT

←Older revision		Revision as of 10:33, 27 March 2024
Line 1:		Line 1:

	==Crystal structure of human MTH1(G2K/D120N mutant) in complex with 8-oxo-dGTP at pH 6.5==		==Crystal structure of human MTH1(G2K/D120N mutant) in complex with 8-oxo-dGTP at pH 6.5==
-	<StructureSection load='6ili' size='340' side='right' caption='[[6ili]], [[Resolution\|resolution]] 1.45Å' scene=''>	+	<StructureSection load='6ili' size='340' side='right'caption='[[6ili]], [[Resolution\|resolution]] 1.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6ili]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ILI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6ILI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6ili]] 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=6ILI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ILI FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name~~=~~'pdbligand=8DG:8~~-~~OXO-2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>8DG</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]] 1.45Å</td></tr>
-	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat">~~[[5ghm\|5ghm]]~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DG:8-OXO-2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>8DG</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=6ili FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ili OCA], [~~http~~://pdbe.org/6ili PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6ili RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6ili PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6ili 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=6ili FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ili OCA], [https://pdbe.org/6ili PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ili RCSB], [https://www.ebi.ac.uk/pdbsum/6ili PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ili 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The human MutT homolog 1 (hMTH1, hNUDT1) hydrolyzes oxidatively damaged nucleoside triphosphates and is the main enzyme responsible for nucleotide sanitization. hMTH1 recently has received attention as an anti-cancer target because hMTH1 blockade leads to accumulation of oxidized nucleotides in the cell, resulting in mutations and death of cancer cells. Unlike Escherichia coli MutT, which shows high substrate specificity for 8-oxoguanine nucleotides, hMTH1 has broad substrate specificity for oxidized nucleotides, including 8-oxo-dGTP and 2-oxo-dATP. However, the reason for this broad substrate specificity remains unclear. Here, we determined crystal structures of hMTH1 in complex with 8-oxo-dGTP or 2-oxo-dATP at neutral pH. These structures based on high-quality data showed that the base moieties of two substrates are located on the similar but not the same position in the substrate-binding pocket and adopt a different hydrogen-bonding pattern and both triphosphate moieties bind to the hMTH1 Nudix motif (i.e. the hydrolase motif) similarly and align for the hydrolysis reaction. We also performed kinetic assays on the substrate-binding Asp120 mutants (D120N and D120A), and determined their crystal structures in complex with the substrates. Analyses of bond-lengths with high-resolution X-ray data and of the relation between the structure and enzymatic activity revealed that hMTH1 recognizes the different oxidized nucleotides via an exchange of the protonation state at two neighboring aspartate residues (Asp119 and Asp120) in its substrate-binding pocket. To our knowledge, this mechanism of broad substrate recognition by enzymes has not been reported previously and may have relevance for anti-cancer drug development strategies targeting hMTH1.	+

-	Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity.,Waz S, Nakamura T, Hirata K, Ogawa YK, Chirifu M, Arimori T, Tamada T, Ikemizu S, Nakabeppu Y, Yamagata Y J Biol Chem. 2016 Dec 29. pii: jbc.M116.749713. doi: 10.1074/jbc.M116.749713. PMID:28035004<ref>PMID:28035004</ref>	+	==See Also==
-		+	*[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures\|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6ili" style~~=~~"background~~-~~color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hirata, K~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Nakabeppu, Y~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Nakamura, T~~]]	+	[[Category: Hirata K]]
-	[[Category: ~~Waz, S]]~~	+	[[Category: Nakabeppu Y]]
-	~~[[Category: Yamagata,~~ Y]]	+	[[Category: Nakamura T]]
-	[[Category: ~~Alpha-beta-alpha sandwich~~]]	+	[[Category: Waz S]]
-	[[Category: ~~Dna damage~~]]	+	[[Category: Yamagata Y]]
-	[[Category: ~~Dna repair]]~~	+
-	~~[[Category: Dna replication]]~~	+
-	~~[[Category: Hydrolase~~]]	+

OCA at 12:23, 7 November 2018

OCA — Wed, 07 Nov 2018 12:23:38 GMT

←Older revision		Revision as of 12:23, 7 November 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6ili is ~~ON HOLD~~	+	==Crystal structure of human MTH1(G2K/D120N mutant) in complex with 8-oxo-dGTP at pH 6.5==
		+	<StructureSection load='6ili' size='340' side='right' caption='[[6ili]], [[Resolution\|resolution]] 1.45Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6ili]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ILI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ILI FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8DG:8-OXO-2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>8DG</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ghm\|5ghm]]</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=6ili FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ili OCA], [http://pdbe.org/6ili PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ili RCSB], [http://www.ebi.ac.uk/pdbsum/6ili PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ili 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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The human MutT homolog 1 (hMTH1, hNUDT1) hydrolyzes oxidatively damaged nucleoside triphosphates and is the main enzyme responsible for nucleotide sanitization. hMTH1 recently has received attention as an anti-cancer target because hMTH1 blockade leads to accumulation of oxidized nucleotides in the cell, resulting in mutations and death of cancer cells. Unlike Escherichia coli MutT, which shows high substrate specificity for 8-oxoguanine nucleotides, hMTH1 has broad substrate specificity for oxidized nucleotides, including 8-oxo-dGTP and 2-oxo-dATP. However, the reason for this broad substrate specificity remains unclear. Here, we determined crystal structures of hMTH1 in complex with 8-oxo-dGTP or 2-oxo-dATP at neutral pH. These structures based on high-quality data showed that the base moieties of two substrates are located on the similar but not the same position in the substrate-binding pocket and adopt a different hydrogen-bonding pattern and both triphosphate moieties bind to the hMTH1 Nudix motif (i.e. the hydrolase motif) similarly and align for the hydrolysis reaction. We also performed kinetic assays on the substrate-binding Asp120 mutants (D120N and D120A), and determined their crystal structures in complex with the substrates. Analyses of bond-lengths with high-resolution X-ray data and of the relation between the structure and enzymatic activity revealed that hMTH1 recognizes the different oxidized nucleotides via an exchange of the protonation state at two neighboring aspartate residues (Asp119 and Asp120) in its substrate-binding pocket. To our knowledge, this mechanism of broad substrate recognition by enzymes has not been reported previously and may have relevance for anti-cancer drug development strategies targeting hMTH1.

-	~~Authors: Nakamura, T~~., Waz, S., ~~Hirata~~, K., ~~Nakabeppu~~, Y., Yamagata, Y.	+	Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity.,Waz S, Nakamura T, Hirata K, Ogawa YK, Chirifu M, Arimori T, Tamada T, Ikemizu S, Nakabeppu Y, Yamagata Y J Biol Chem. 2016 Dec 29. pii: jbc.M116.749713. doi: 10.1074/jbc.M116.749713. PMID:28035004<ref>PMID:28035004</ref>

-	~~Description: Crystal structure~~ of ~~human MTH1(G2K~~/~~D120N mutant) in complex with 8~~-~~oxo~~-~~dGTP~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 6ili" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Hirata, K]]
	[[Category: Nakabeppu, Y]]		[[Category: Nakabeppu, Y]]
-	[[Category: Yamagata, Y]]
-	[[Category: Waz, S]]
	[[Category: Nakamura, T]]		[[Category: Nakamura, T]]
-	[[Category: ~~Hirata~~, K]]	+	[[Category: Waz, S]]
		+	[[Category: Yamagata, Y]]
		+	[[Category: Alpha-beta-alpha sandwich]]
		+	[[Category: Dna damage]]
		+	[[Category: Dna repair]]
		+	[[Category: Dna replication]]
		+	[[Category: Hydrolase]]

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

OCA — Wed, 24 Oct 2018 04:25:37 GMT

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

←Older revision

Revision as of 04:25, 24 October 2018

OCA: New page: '''Unreleased structure''' The entry 6ili is ON HOLD Authors: Nakamura, T., Waz, S., Hirata, K., Nakabeppu, Y., Yamagata, Y. Description: Crystal structure of human MTH1(G2K/D120N muta...

OCA — Wed, 24 Oct 2018 04:25:35 GMT

New page: '''Unreleased structure''' The entry 6ili is ON HOLD Authors: Nakamura, T., Waz, S., Hirata, K., Nakabeppu, Y., Yamagata, Y. Description: Crystal structure of human MTH1(G2K/D120N muta...

New page

'''Unreleased structure'''

The entry 6ili is ON HOLD

Authors: Nakamura, T., Waz, S., Hirata, K., Nakabeppu, Y., Yamagata, Y.

Description: Crystal structure of human MTH1(G2K/D120N mutant) in complex with 8-oxo-dGTP
[[Category: Unreleased Structures]]
[[Category: Nakabeppu, Y]]
[[Category: Yamagata, Y]]
[[Category: Waz, S]]
[[Category: Nakamura, T]]
[[Category: Hirata, K]]