5DFI

Human APE1 phosphorothioate substrate complex

Summary for 5DFI

• Entry DOI: 10.2210/pdb5dfi/pdb
• Related: 5DFF 5DFH 5DFJ
• Descriptor: DNA-(apurinic or apyrimidinic site) lyase, DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*(OMC)P*(48Z)P*CP*GP*AP*CP*GP*GP*AP*TP*CP*C)-3'), DNA (5'-D(*GP*GP*AP*TP*CP*CP*GP*TP*CP*GP*GP*GP*CP*GP*CP*AP*TP*CP*AP*GP*C)-3'), ... (6 entities in total)
• Functional Keywords: hydrolase, lyase/dna, lyase-dna complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 75681.68

Authors

Freudenthal, B.D.,Wilson, S.H. (deposition date: 2015-08-26, release date: 2015-10-14, Last modification date: 2024-03-13)

Primary citation

Freudenthal, B.D.,Beard, W.A.,Cuneo, M.J.,Dyrkheeva, N.S.,Wilson, S.H.
Capturing snapshots of APE1 processing DNA damage.
Nat.Struct.Mol.Biol., 22:924-931, 2015

PubMed Abstract: DNA apurinic-apyrimidinic (AP) sites are prevalent noncoding threats to genomic stability and are processed by AP endonuclease 1 (APE1). APE1 incises the AP-site phosphodiester backbone, generating a DNA-repair intermediate that is potentially cytotoxic. The molecular events of the incision reaction remain elusive, owing in part to limited structural information. We report multiple high-resolution human APE1-DNA structures that divulge new features of the APE1 reaction, including the metal-binding site, the nucleophile and the arginine clamps that mediate product release. We also report APE1-DNA structures with a T-G mismatch 5' to the AP site, representing a clustered lesion occurring in methylated CpG dinucleotides. These structures reveal that APE1 molds the T-G mismatch into a unique Watson-Crick-like geometry that distorts the active site, thus reducing incision. These snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.

PubMed: 26458045
DOI: 10.1038/nsmb.3105

Experimental method

X-RAY DIFFRACTION (1.63 Å)