4hno | pdb_00004hno
High resolution crystal structure of DNA Apurinic/apyrimidinic (AP) endonuclease IV Nfo from Thermatoga maritima
Structural highlights
FunctionEND4_THEMA Endonuclease IV plays a role in DNA repair. It cleaves phosphodiester bonds at apurinic or apyrimidinic sites (AP sites) to produce new 5'-ends that are base-free deoxyribose 5-phosphate residues. It preferentially attacks modified AP sites created by bleomycin and neocarzinostatin (By similarity). Publication Abstract from PubMedNon-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion. Yet, they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 A resolution APE1-DNA product complex with Mg2+ and a 0.92 A Nfo with three metal ions. Structural and biochemical comparions of these two evolutionarily distinct enzymes, characterize key APE1 catalytic residues that are potentially functionally similar to Nfo active site components. as further tested and supported by computational analyses. We observe a Mg-water cluster in the APE1 active site, with only Glu96 forming the only direct protein coordination to the Mg2+. Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collective results enlighten activities of residues, metal ions, and active site features for abasic site endonucleases. Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyirmidince Endonuclease APE1 and Endonuclease IV DNA repair enzymes.,Tsutakawa SE, Shin DS, Mol CD, Izumi T, Arvai AS, Mantha AK, Szczesny B, Ivanov IN, Hosfield DJ, Maiti B, Pique ME, Frankel KA, Hitomi K, Cunningham RP, Mitra S, Tainer JA J Biol Chem. 2013 Jan 25. PMID:23355472[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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