4u6p | pdb_00004u6p

Structural mechanism of error-free bypass of major benzo[a]pyrene adduct by human polymerase kappa

spinqualitylabelsall models 4u6p, resolution 2.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4u6p is a 6 chain structure with sequence from Homo sapiens and Unidentified. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.593Å Ligands: DCT, MG, PGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function POLK_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. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. Publication Abstract from PubMed Benzo[a]pyrene (BP) is a well-known and frequently encountered carcinogen which generates a bulky DNA adduct (+)-trans-10S-BP-N2-dG (BP-dG) in cells. DNA polymerase kappa (polkappa) is the only known Y-family polymerase that bypasses BP-dG accurately and thus protects cells from genotoxic BP. Here, we report the structures of human polkappa in complex with DNA containing either a normal guanine (G) base or a BP-dG adduct at the active site and a correct deoxycytidine. The structures and supporting biochemical data reveal a unique mechanism for accurate replication by translesion synthesis past the major bulky adduct. The active site of polkappa opens at the minor groove side of the DNA substrate to accommodate the bulky BP-dG that is attached there. More importantly, polkappa stabilizes the lesion DNA substrate in the same active conformation as for regular B-form DNA substrates and the bulky BPDE ring in a 5' end pointing conformation. The BP-dG adducted DNA substrate maintains a Watson-Crick (BP-dG:dC) base pair within the active site, governing correct nucleotide insertion opposite the bulky adduct. In addition, polkappa's unique N-clasp domain supports the open conformation of the enzyme and the extended conformation of the single-stranded template to allow bypass of the bulky lesion. This work illustrates the first molecular mechanism for how a bulky major adduct is replicated accurately without strand misalignment and mis-insertion. Structure and mechanism of error-free replication past the major benzo[a]pyrene adduct by human DNA polymerase kappa.,Jha V, Bian C, Xing G, Ling H Nucleic Acids Res. 2016 Mar 31. pii: gkw204. PMID:27034468 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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