6sqw

From Proteopedia

(Difference between revisions)

Current revision

Mouse dCTPase in complex with 5-Me-dCMP

Structural highlights

6sqw is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	Dctpp1, Tdrg-TL1 (LK3 transgenic mice)
Activity:	dCTP diphosphatase, with EC number 3.6.1.12
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wu B, Liu Y, Zhao Q, Liao S, Zhang J, Bartlam M, Chen W, Rao Z. Crystal structure of RS21-C6, involved in nucleoside triphosphate pyrophosphohydrolysis. J Mol Biol. 2007 Apr 13;367(5):1405-12. Epub 2007 Jan 26. PMID:17320107 doi:10.1016/j.jmb.2007.01.057
↑ Nonaka M, Tsuchimoto D, Sakumi K, Nakabeppu Y. Mouse RS21-C6 is a mammalian 2'-deoxycytidine 5'-triphosphate pyrophosphohydrolase that prefers 5-iodocytosine. FEBS J. 2009 Mar;276(6):1654-66. doi: 10.1111/j.1742-4658.2009.06898.x. Epub 2009, Feb 7. PMID:19220460 doi:http://dx.doi.org/10.1111/j.1742-4658.2009.06898.x
↑ Scaletti E, Claesson M, Helleday T, Jemth AS, Stenmark P. The first structure of an active mammalian dCTPase and its complexes with substrate analogues and products. J Mol Biol. 2020 Jan 15. pii: S0022-2836(20)30024-3. doi:, 10.1016/j.jmb.2020.01.005. PMID:31954130 doi:http://dx.doi.org/10.1016/j.jmb.2020.01.005

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6sqw"

@@ Line 3: / Line 3: @@
 <StructureSection load='6sqw' size='340' side='right'caption='[[6sqw]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6sqw]] is a 2 chain structure. 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>
+<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>
@@ Line 24: / Line 25: @@
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: DCTP diphosphatase]]
 [[Category: Claesson, M]]

6sqw

From Proteopedia

Current revision

Mouse dCTPase in complex with 5-Me-dCMP

Structural highlights

Function

Publication Abstract from PubMed

References

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