6pz3
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Polymerase Eta-catalyzed insertion of correct G opposite template cytarabine (AraC) residue== | |
| + | <StructureSection load='6pz3' size='340' side='right'caption='[[6pz3]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6pz3]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PZ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PZ3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=XG4:2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]GUANOSINE'>XG4</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAR:CYTOSINE+ARABINOSE-5-PHOSPHATE'>CAR</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </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=6pz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pz3 OCA], [http://pdbe.org/6pz3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pz3 RCSB], [http://www.ebi.ac.uk/pdbsum/6pz3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pz3 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN]] Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM:[http://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 == | ||
| + | [[http://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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Poldelta is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Poleta is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Poleta with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Poleta can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Poleta to promote AraC induced mutagenesis in relapsed AML patients. | ||
| - | + | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase eta.,Rechkoblit O, Johnson RE, Buku A, Prakash L, Prakash S, Aggarwal AK Sci Rep. 2019 Nov 8;9(1):16400. doi: 10.1038/s41598-019-52703-7. PMID:31704958<ref>PMID:31704958</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6pz3" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: DNA-directed DNA polymerase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Aggarwal, A K]] | ||
| + | [[Category: Rechkoblit, O]] | ||
| + | [[Category: Chemotherapy]] | ||
| + | [[Category: Cytarabin]] | ||
| + | [[Category: Dna damage]] | ||
| + | [[Category: Lesion bypass]] | ||
| + | [[Category: Replication]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 15:33, 20 November 2019
Polymerase Eta-catalyzed insertion of correct G opposite template cytarabine (AraC) residue
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