4mf2

Structure of human DNA polymerase beta complexed with O6MG as the template base in a 1-nucleotide gapped DNA

spinqualitylabelsall models 4mf2, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mf2 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA NonStd Res: 6OG Related: 3isb, 1bpx, 4mf8, 4mfa, 4mfc, 4mff Gene: POLB (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DPOLB_HUMAN] Repair polymerase that plays a key role in base-excision repair. Has 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity that removes the 5' sugar phosphate and also acts as a DNA polymerase that adds one nucleotide to the 3' end of the arising single-nucleotide gap. Conducts 'gap-filling' DNA synthesis in a stepwise distributive fashion rather than in a processive fashion as for other DNA polymerases. Publication Abstract from PubMed Human DNA polymerase beta (polbeta) inserts, albeit slowly, T opposite the carcinogenic lesion O6-methylguanine (O6MeG) approximately 30-fold more frequently than C. To gain insight into this promutagenic process, we solved four ternary structures of polbeta with an incoming dCTP or dTTP analogue base-paired with O6MeG in the presence of active-site Mg2+ or Mn2+. The Mg2+-bound structures show that both the O6MeG.dCTP/dTTP-Mg2+ complexes adopt an open protein conformation, staggered base pair, and one active-site metal ion. The Mn2+-bound structures reveal that, whereas the O6Me.dCTP-Mn2+ complex assumes the similar altered conformation, the O6MeG.dTTP-Mn2+ complex adopts a catalytically competent state with a closed protein conformation and pseudo-Watson-Crick base pair. On the basis of these observations, we conclude that polbeta slows nucleotide incorporation opposite O6MeG by inducing an altered conformation suboptimal for catalysis and promotes mutagenic replication by allowing Watson-Crick-mode for O6MeG.T but not for O6MeG.C in the enzyme active site. The O6MeG.dTTP-Mn2+ ternary structure, which represents the first structure of mismatched polbeta ternary complex with a closed protein conformation and coplanar base pair, the first structure of pseudo-Watson-Crick O6MeG.T formed in the active site of a DNA polymerase, and a rare, if not the first, example of metal-dependent conformational activation of a DNA polymerase, indicate that catalytic metal-ion coordination is utilized as a kinetic checkpoint by polbeta and is crucial for the conformational activation of polbeta. Overall, our structural studies not only explain the promutagenic polbeta catalysis across O6MeG but also provide new insights into the replication fidelity of polbeta. Metal-Dependent Conformational Activation Explains Highly Promutagenic Replication across O6-Methylguanine by Human DNA Polymerase beta,Koag MC, Lee S J Am Chem Soc. 2014 Apr 2. PMID:24694247 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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