View source for 8gla


==Co-crystal structure of caPCNA bound to the AOH1996 derivative, AOH1996-1LE==
<StructureSection load='8gla' size='340' side='right'caption='[[8gla]], [[Resolution|resolution]] 3.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8gla]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GLA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GLA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.77&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=ZQZ:N-[2-(3-methoxyphenoxy)phenyl]-N~2~-(naphthalene-1-carbonyl)-L-alpha-glutamine'>ZQZ</scene></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=8gla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gla OCA], [https://pdbe.org/8gla PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gla RCSB], [https://www.ebi.ac.uk/pdbsum/8gla PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gla ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PCNA_HUMAN PCNA_HUMAN] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.<ref>PMID:19443450</ref> <ref>PMID:18719106</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.

Small molecule targeting of transcription-replication conflict for selective chemotherapy.,Gu L, Li M, Li CM, Haratipour P, Lingeman R, Jossart J, Gutova M, Flores L, Hyde C, Kenjic N, Li H, Chung V, Li H, Lomenick B, Von Hoff DD, Synold TW, Aboody KS, Liu Y, Horne D, Hickey RJ, Perry JJP, Malkas LH Cell Chem Biol. 2023 Oct 19;30(10):1235-1247.e6. doi: , 10.1016/j.chembiol.2023.07.001. Epub 2023 Aug 1. PMID:37531956<ref>PMID:37531956</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8gla" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proliferating cell nuclear antigen 3D structures|Proliferating cell nuclear antigen 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jossart J]]
[[Category: Perry JJ]]