4iem | pdb_00004iem

Human apurinic/apyrimidinic endonuclease (APE1) with product DNA and Mg2+

spinqualitylabelsall models 4iem, resolution 2.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4iem is a 16 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3DR, MG, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function APEX1_HUMAN Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA. Publication Abstract from PubMed Non-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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Apurinic/apyrimidinic endonuclease 3D structures

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