View source for 5dgb


==CRYSTAL STRUCTURE OF HUMAN DNA POLYMERASE ETA EXTENDING AN 1,N6-ETHENODEOXYADENOSINE : dA PAIR BY INSERTING dTMPNPP OPPOSITE TEMPLATE dA==
<StructureSection load='5dgb' size='340' side='right'caption='[[5dgb]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5dgb]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DGB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DGB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1FZ:5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]THYMIDINE'>1FZ</scene>, <scene name='pdbligand=EDA:3-[2-DEOXY-RIBOFURANOSYL]-3H-1,3,4,5A,8-PENTAAZA-AS-INDACENE-5-MONOPHOSPHATE'>EDA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5dgb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dgb OCA], [https://pdbe.org/5dgb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dgb RCSB], [https://www.ebi.ac.uk/pdbsum/5dgb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dgb ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN] Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM:[https://omim.org/entry/278750 278750]; also designated as XP-V. Xeroderma pigmentosum (XP) is an autosomal recessive disease due to deficient nucleotide excision repair. It is characterized by hypersensitivity of the skin to sunlight, followed by high incidence of skin cancer and frequent neurologic abnormalities. XPV shows normal nucleotide excision repair, but an exaggerated delay in recovery of replicative DNA synthesis. Most XPV patients do not develop clinical symptoms and skin neoplasias until a later age. Clinical manifestations are limited to photo-induced deterioration of the skin and eyes.<ref>PMID:10385124</ref> <ref>PMID:10398605</ref> <ref>PMID:11032022</ref> <ref>PMID:11121129</ref> <ref>PMID:11773631</ref> 
== Function ==
[https://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Plays an important role in the repair of UV-induced pyrimidine dimers. Depending on the context, it inserts the correct base, but causes frequent base transitions and transversions. May play a role in hypermutation at immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. Targets POLI to replication foci.<ref>PMID:10385124</ref> <ref>PMID:11743006</ref> <ref>PMID:11376341</ref> <ref>PMID:14630940</ref> <ref>PMID:14734526</ref> 
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== Publication Abstract from PubMed ==
1,N6-Ethenodeoxyadenosine (1,N6-epsilondA) is the major etheno lesion formed in the reaction of DNA with epoxides substituted with good leaving groups (e.g., vinyl chloride epoxide). This lesion is also formed endogenously in DNA from lipid oxidation. Recombinant human DNA polymerase eta (hpol eta) can replicate oligonucleotide templates containing 1,N6-epsilondA. In steady-state kinetic analysis, hpol eta preferred to incorporate dATP and dGTP, compared to dTTP. Mass spectral analysis of incorporation products also showed preferred purine (A, G) incorporation and extensive -1 frameshifts, suggesting pairing of the inserted purine and slippage before further replication. Five X-ray crystal structures of hpol eta ternary complexes were determined, three at the insertion and two at the extension stage. Two insertion complexes revealed incoming non-hydrolyzable dATP or dGTP analogs not pairing with but instead in a staggered configuration relative to 1,N6-epsilondA in the anti conformation, thus opposite the 5 prime-T in the template, explaining the proclivity for frameshift misincorporation. In another insertion complex, dTTP was positioned opposite 1,N6-epsilondA and the adduct base was in the syn conformation, with formation of two hydrogen bonds. At the extension stage, with either an incorporated dA or dT opposite 1,N6-epsilondA and dTMPNPP opposite the 5 prime-A, the 3 prime-terminal nucleoside of the primer was disordered, consistent with the tendency not to incorporate dTTP opposite 1,N6-epsilondA. Collectively the results show a preference for purine pairing opposite 1,N6-epsilondA and for -1 frameshifts.

Structural and Kinetic Analysis of Miscoding Opposite the DNA Adduct 1,N6-Ethenodeoxyadenosine by Human Translesion DNA Polymerase eta.,Patra A, Su Y, Zhang Q, Johnson KM, Guengerich FP, Egli M J Biol Chem. 2016 May 16. pii: jbc.M116.732487. PMID:27226627<ref>PMID:27226627</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Egli M]]
[[Category: Patra A]]