6d0z

Polymerase Eta cytarabine (AraC) extension ternary complex

spinqualitylabelsall models 6d0z, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d0z is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DZ4, GOL, MG NonStd Res: CAR Related: 6d0m Gene: POLH, RAD30, RAD30A, XPV (HUMAN) Activity: DNA-directed DNA polymerase, with EC number 2.7.7.7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [POLH_HUMAN] Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM: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. Function [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. Publication Abstract from PubMed Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2'-deoxycytidine only by the presence of an additional hydroxyl group at the C2' position of the 2'-deoxyribose. The active form of the drug AraC 5'-triphosphate (AraCTP) is utilized by human replicative DNA polymerases to insert AraC at the 3' terminus of a growing DNA chain. This impedes further primer extension and is a primary basis for the drug action. The Y-family translesion synthesis (TLS) DNA polymerase eta (Poleta) counteracts this barrier to DNA replication by efficient extension from AraC-terminated primers. Here, we provide high-resolution structures of human Poleta with AraC incorporated at the 3'-primer terminus. We show that Poleta can accommodate AraC at different stages of the catalytic cycle, and that it can manipulate the conformation of the AraC sugar via specific hydrogen bonding and stacking interactions. Taken together, the structures provide a basis for the ability of Poleta to extend DNA synthesis from AraC terminated primers. Structural basis for polymerase eta-promoted resistance to the anticancer nucleoside analog cytarabine.,Rechkoblit O, Choudhury JR, Buku A, Prakash L, Prakash S, Aggarwal AK Sci Rep. 2018 Aug 23;8(1):12702. doi: 10.1038/s41598-018-30796-w. PMID:30140014 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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