7lpi

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==APE1 phosphorothioate substrate complex with abasic ribonucleotide DNA==
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<StructureSection load='7lpi' size='340' side='right'caption='[[7lpi]]' scene=''>
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<StructureSection load='7lpi' size='340' side='right'caption='[[7lpi]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7lpi]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LPI FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lpi OCA], [https://pdbe.org/7lpi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lpi RCSB], [https://www.ebi.ac.uk/pdbsum/7lpi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lpi ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YA4:[(2~{R},3~{S},4~{S})-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-sulfanyl-phosphinic+acid'>YA4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lpi OCA], [https://pdbe.org/7lpi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lpi RCSB], [https://www.ebi.ac.uk/pdbsum/7lpi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lpi ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/APEX1_HUMAN 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.<ref>PMID:1719477</ref> <ref>PMID:12524539</ref> <ref>PMID:8355688</ref> <ref>PMID:8621488</ref> <ref>PMID:8932375</ref> <ref>PMID:9108029</ref> <ref>PMID:9207062</ref> <ref>PMID:9804799</ref> <ref>PMID:9560228</ref> <ref>PMID:10023679</ref> <ref>PMID:11118054</ref> <ref>PMID:11452037</ref> <ref>PMID:11832948</ref> <ref>PMID:11809897</ref> <ref>PMID:16617147</ref> <ref>PMID:18439621</ref> <ref>PMID:18809583</ref> <ref>PMID:18179823</ref> <ref>PMID:18579163</ref> <ref>PMID:19188445</ref> <ref>PMID:19401441</ref> <ref>PMID:19934257</ref> <ref>PMID:20699270</ref> <ref>PMID:21496894</ref> <ref>PMID:21762700</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Ribonucleotides (rNTPs) are predicted to be incorporated into the genome at a rate of up to 3 million times per cell division, making rNTPs the most common non-standard nucleotide in the human genome. Typically, misinserted ribonucleotides are repaired by the ribonucleotide excision repair (RER) pathway, which is initiated by RNase H2 cleavage. However, rNTPs are susceptible to spontaneous depurination generating abasic ribonucleotides (rAPs), which are unable to be processed by RNase H2. Additionally, rAPs have been found in nascent RNA and coupled to R-loops. Recent work identified that base excision repair (BER) protein AP-Endonuclease 1 (APE1) is responsible for the initial processing of rAPs embedded in DNA and in R-loops. APE1 is a well characterized AP endonuclease that cleaves 5' of abasic sites, but its ability to cleave at rAPs remains poorly understood. Here, we utilize enzyme kinetics, X-ray crystallography, and molecular dynamics simulations to provide insight into rAP processing by APE1. Enzyme kinetics were used to determine pre-steady-state rates of APE1 cleavage on DNA substrates containing rAP, revealing a decrease in activity compared to cleavage at a canonical deoxy-AP substrate. Using X-ray crystallography, we identified novel contacts between the rAP and the APE1 active site. We demonstrate that the rAP sugar pucker is accommodated in the active site in a C3'-endo conformation, influencing its position and contributing to a decrease in activity compared to the deoxy-AP site. Together, this work provides molecular level insights into rAP processing by APE1 and advances our understanding of ribonucleotide processing within genomic DNA.
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Altered APE1 activity on abasic ribonucleotides is mediated by changes in the nucleoside sugar pucker.,Hoitsma NM, Click TH, Agarwal PK, Freudenthal BD Comput Struct Biotechnol J. 2021 May 25;19:3293-3302. doi: , 10.1016/j.csbj.2021.05.035. eCollection 2021. PMID:34188778<ref>PMID:34188778</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7lpi" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Apurinic/apyrimidinic endonuclease 3D structures|Apurinic/apyrimidinic endonuclease 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Synthetic construct]]
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[[Category: Freudenthal BD]]
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[[Category: Hoitsma NM]]

Current revision

APE1 phosphorothioate substrate complex with abasic ribonucleotide DNA

PDB ID 7lpi

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