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3sq8

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Revision as of 08:26, 4 August 2016

Crystal Structure Analysis of the Yeast Tyrosyl-DNA Phosphodiesterase 1 H432R Mutant (SCAN1 Mutant)

Structural highlights

3sq8 is a 4 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Related:	1q32, 3sq3, 3sq5, 3sq7
Gene:	TDP1, YBR223C, YBR1520 (Baker's yeast)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TYDP1_YEAST] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Cleaves also 5' phosphotyrosyl adducts resulting from dead-end complexes between DNA and the active site tyrosine of topoisomerase II. Contributes to DNA repair after radiation damage. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. May have low 3'exonuclease activity and may be able to remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate (By similarity).^[1] ^[2]

Publication Abstract from PubMed

Tyrosyl-DNA phosphodiesterase I (Tdp1) is a member of the phospholipase D superfamily that hydrolyzes 3'-phospho-DNA adducts via two conserved catalytic histidines-one acting as the lead nucleophile and the second acting as a general acid/base. Substitution of the second histidine specifically to arginine contributes to the neurodegenerative disease spinocerebellar ataxia with axonal neuropathy (SCAN1). We investigated the catalytic role of this histidine in the yeast protein (His432) using a combination of X-ray crystallography, biochemistry, yeast genetics, and theoretical chemistry. The structures of wild-type Tdp1 and His432Arg both show a phosphorylated form of the nucleophilic histidine that is not observed in the structure of His432Asn. The phosphohistidine is stabilized in the His432Arg structure by the guanidinium group that also restricts the access of nucleophilic water molecule to the Tdp1-DNA intermediate. Biochemical analyses confirm that His432Arg forms an observable and unique Tdp1-DNA adduct during catalysis. Substitution of His432 by Lys does not affect catalytic activity or yeast phenotype, but substitutions with Asn, Gln, Leu, Ala, Ser, and Thr all result in severely compromised enzymes and DNA topoisomerase I-camptothecin dependent lethality. Surprisingly, His432Asn did not show a stable covalent Tdp1-DNA intermediate that suggests another catalytic defect. Theoretical calculations revealed that the defect resides in the nucleophilic histidine and that the pK(a) of this histidine is crucially dependent on the second histidine and on the incoming phosphate of the substrate. This represents a unique example of substrate-activated catalysis that applies to the entire phospholipase D superfamily.

Analysis of the Active-Site Mechanism of Tyrosyl-DNA Phosphodiesterase I: A Member of the Phospholipase D Superfamily.,Gajewski S, Comeaux EQ, Jafari N, Bharatham N, Bashford D, White SW, van Waardenburg RC J Mol Biol. 2011 Dec 6. PMID:22155078^[3]

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

References

↑ Pouliot JJ, Yao KC, Robertson CA, Nash HA. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science. 1999 Oct 15;286(5439):552-5. PMID:10521354
↑ Nitiss KC, Malik M, He X, White SW, Nitiss JL. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):8953-8. Epub 2006 Jun 2. PMID:16751265 doi:http://dx.doi.org/0603455103
↑ Gajewski S, Comeaux EQ, Jafari N, Bharatham N, Bashford D, White SW, van Waardenburg RC. Analysis of the Active-Site Mechanism of Tyrosyl-DNA Phosphodiesterase I: A Member of the Phospholipase D Superfamily. J Mol Biol. 2011 Dec 6. PMID:22155078 doi:10.1016/j.jmb.2011.11.044

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3sq8"

@@ Line 1: / Line 1: @@
 ==Crystal Structure Analysis of the Yeast Tyrosyl-DNA Phosphodiesterase 1 H432R Mutant (SCAN1 Mutant)==
 <StructureSection load='3sq8' size='340' side='right' caption='[[3sq8]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3sq8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SQ8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3sq8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SQ8 FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NEP:N1-PHOSPHONOHISTIDINE'>NEP</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1q32|1q32]], [[3sq3|3sq3]], [[3sq5|3sq5]], [[3sq7|3sq7]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TDP1, YBR223C, YBR1520 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TDP1, YBR223C, YBR1520 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast])</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=3sq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sq8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sq8 RCSB], [http://www.ebi.ac.uk/pdbsum/3sq8 PDBsum]</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=3sq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sq8 OCA], [http://pdbe.org/3sq8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3sq8 RCSB], [http://www.ebi.ac.uk/pdbsum/3sq8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3sq8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3sq8" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Saccharomyces cerevisiae]]
+[[Category: Baker's yeast]]
 [[Category: Gajewski, S]]
 [[Category: White, S W]]

3sq8

From Proteopedia

Revision as of 08:26, 4 August 2016

Crystal Structure Analysis of the Yeast Tyrosyl-DNA Phosphodiesterase 1 H432R Mutant (SCAN1 Mutant)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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