6sqw: Difference between revisions
New page: '''Unreleased structure''' The entry 6sqw is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Mouse dCTPase in complex with 5-Me-dCMP== | ||
<StructureSection load='6sqw' size='340' side='right'caption='[[6sqw]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6sqw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SQW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SQW FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5CM:5-METHYL-2-DEOXY-CYTIDINE-5-MONOPHOSPHATE'>5CM</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">Dctpp1, Tdrg-TL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dCTP_diphosphatase dCTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.12 3.6.1.12] </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=6sqw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sqw OCA], [http://pdbe.org/6sqw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6sqw RCSB], [http://www.ebi.ac.uk/pdbsum/6sqw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6sqw ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/DCTP1_MOUSE DCTP1_MOUSE]] Hydrolyzes deoxynucleoside triphosphates (dNTPs) to the corresponding nucleoside monophosphates. Has a strong preference for modified dCTP. Activity is highest with 5-iodo-dCTP, followed by 5-bromo-dCTP, unmodified dCTP, 5-methyl-dCTP and 5-chloro-dCTP. Hydrolyzes 2-chloro-dATP and 2-hydroxy-dATP with lower efficiency, and has even lower activity with unmodified dATP, dTTP and dUTP (in vitro). Does not hydrolyze ATP, UTP, ITP, GTP, dADP, dCDP or dGTP. May protect DNA or RNA against the incorporation of non-canonical nucleotide triphosphates. May protect cells against inappropriate methylation of CpG islands by DNA methyltransferases.<ref>PMID:17320107</ref> <ref>PMID:19220460</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Precise regulation of dNTPs within the cellular nucleotide pool is essential for high accuracy of DNA replication and is critical for retaining the genomic integrity. Recently, human dCTPase (deoxycytidine triphosphatase), also known as DCTPP1 (human all-alpha dCTP pyrophosphatase 1) has been revealed to be a key player in the balance of pyrimidine nucleotide concentrations within cells, with DCTPP1 deficiency causing DNA damage and genetic instability in both chromosomal and mitochondrial DNA. DCTPP1 also exhibits an additional 'house cleaning' function as it has been shown to be highly active against modified cytidine trinucleotides such as 5-methyl-dCTP, which if incorrectly incorporated into DNA can introduce undesirable epigenetic marking. To date, structural studies of mammalian dCTPase have been limited to inactive constructs, which do not provide information regarding the catalytic mechanism of this important enzyme. We here present the first structures of an active mammalian dCTPase from M. musculus in complex with the non-hydrolysable substrate analogue dCMPNPP and the products 5-Me-dCMP and dCMP. These structures provide clear insights into substrate binding and catalysis, and clearly elucidate why previous structures of mammalian dCTPase were catalytically inactive. The overall structure of M. musculus dCTPase is highly similar to enzymes from the all-alpha NTP phosphohydrolase superfamily. Comparison of M. musculus dCTPase with homologues from a diverse range of mammals including humans, show that the residues which contribute to substrate recognition are entirely conserved, further supporting the importance of this enzyme in the protection of genomic integrity in mammalian cells. | |||
The first structure of an active mammalian dCTPase and its complexes with substrate analogues and products.,Scaletti E, Claesson M, Helleday T, Jemth AS, Stenmark P J Mol Biol. 2020 Jan 15. pii: S0022-2836(20)30024-3. doi:, 10.1016/j.jmb.2020.01.005. PMID:31954130<ref>PMID:31954130</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6sqw" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Lk3 transgenic mice]] | |||
[[Category: DCTP diphosphatase]] | |||
[[Category: Claesson, M]] | |||
[[Category: Helleday, H]] | |||
[[Category: Jemth, A S]] | |||
[[Category: Scaletti, E R]] | |||
[[Category: Stenmark, P]] | |||
[[Category: 5-me-dcmp complex]] | |||
[[Category: Hydrolase]] | |||
Latest revision as of 11:04, 11 March 2020
Mouse dCTPase in complex with 5-Me-dCMPMouse dCTPase in complex with 5-Me-dCMP
Structural highlights
Function[DCTP1_MOUSE] Hydrolyzes deoxynucleoside triphosphates (dNTPs) to the corresponding nucleoside monophosphates. Has a strong preference for modified dCTP. Activity is highest with 5-iodo-dCTP, followed by 5-bromo-dCTP, unmodified dCTP, 5-methyl-dCTP and 5-chloro-dCTP. Hydrolyzes 2-chloro-dATP and 2-hydroxy-dATP with lower efficiency, and has even lower activity with unmodified dATP, dTTP and dUTP (in vitro). Does not hydrolyze ATP, UTP, ITP, GTP, dADP, dCDP or dGTP. May protect DNA or RNA against the incorporation of non-canonical nucleotide triphosphates. May protect cells against inappropriate methylation of CpG islands by DNA methyltransferases.[1] [2] Publication Abstract from PubMedPrecise regulation of dNTPs within the cellular nucleotide pool is essential for high accuracy of DNA replication and is critical for retaining the genomic integrity. Recently, human dCTPase (deoxycytidine triphosphatase), also known as DCTPP1 (human all-alpha dCTP pyrophosphatase 1) has been revealed to be a key player in the balance of pyrimidine nucleotide concentrations within cells, with DCTPP1 deficiency causing DNA damage and genetic instability in both chromosomal and mitochondrial DNA. DCTPP1 also exhibits an additional 'house cleaning' function as it has been shown to be highly active against modified cytidine trinucleotides such as 5-methyl-dCTP, which if incorrectly incorporated into DNA can introduce undesirable epigenetic marking. To date, structural studies of mammalian dCTPase have been limited to inactive constructs, which do not provide information regarding the catalytic mechanism of this important enzyme. We here present the first structures of an active mammalian dCTPase from M. musculus in complex with the non-hydrolysable substrate analogue dCMPNPP and the products 5-Me-dCMP and dCMP. These structures provide clear insights into substrate binding and catalysis, and clearly elucidate why previous structures of mammalian dCTPase were catalytically inactive. The overall structure of M. musculus dCTPase is highly similar to enzymes from the all-alpha NTP phosphohydrolase superfamily. Comparison of M. musculus dCTPase with homologues from a diverse range of mammals including humans, show that the residues which contribute to substrate recognition are entirely conserved, further supporting the importance of this enzyme in the protection of genomic integrity in mammalian cells. The first structure of an active mammalian dCTPase and its complexes with substrate analogues and products.,Scaletti E, Claesson M, Helleday T, Jemth AS, Stenmark P J Mol Biol. 2020 Jan 15. pii: S0022-2836(20)30024-3. doi:, 10.1016/j.jmb.2020.01.005. PMID:31954130[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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