1de8
HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE-1 (APE1) BOUND TO ABASIC DNA
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OverviewOverview
Non-coding apurinic/apyrimidinic (AP) sites in DNA are continually created, in cells both spontaneously and by damage-specific DNA glycosylases. The, biologically critical human base excision repair enzyme APE1 cleaves the, DNA sugar-phosphate backbone at a position 5' of AP sites to prime DNA, repair synthesis. Here we report three co-crystal structures of human APE1, bound to abasic DNA which show that APE1 uses a rigid, pre-formed, positively charged surface to kink the DNA helix and engulf the AP-DNA, strand. APE1 inserts loops into both the DNA major and minor grooves and, binds a flipped-out AP site in a pocket that excludes DNA bases and, racemized beta-anomer AP sites. Both the APE1 active-site geometry and a, complex with cleaved AP-DNA and Mn2+ support a testable structure-based, catalytic mechanism. Alanine substitutions of the residues that penetrate, the DNA helix unexpectedly show that human APE1 is structurally optimized, to retain the cleaved DNA product. These structural and mutational results, show how APE1 probably displaces bound glycosylases and retains the nicked, DNA product, suggesting that APE1 acts in vivo to coordinate the orderly, transfer of unstable DNA damage intermediates between the excision and, synthesis steps of DNA repair.
DiseaseDisease
Known diseases associated with this structure: Autoimmune polyglandular disease, type I OMIM:[607358], Sveinsson choreoretinal atrophy OMIM:[189967]
About this StructureAbout this Structure
1DE8 is a Single protein structure of sequence from Homo sapiens. Active as DNA-(apurinic or apyrimidinic site) lyase, with EC number 4.2.99.18 Full crystallographic information is available from OCA.
ReferenceReference
DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected], Mol CD, Izumi T, Mitra S, Tainer JA, Nature. 2000 Jan 27;403(6768):451-6. PMID:10667800
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