4dl5

Human DNA polymerase eta inserting dCMPNPP opposite the 5'G of cisplatin crosslinked Gs (Pt-GG2).

spinqualitylabelsall models 4dl5, resolution 2.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4dl5 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.92Å Ligands: 0KX, CPT, MG 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 Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase eta (hPol eta). Here, we report crystal structures of hPol eta complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol eta is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol eta differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol eta undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol eta is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol eta is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance. Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin.,Zhao Y, Biertumpfel C, Gregory MT, Hua YJ, Hanaoka F, Yang W Proc Natl Acad Sci U S A. 2012 Apr 23. PMID:22529383 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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