View source for 8a9k


==Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 (consensus reconstruction)==
<StructureSection load='8a9k' size='340' side='right'caption='[[8a9k]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8a9k]] is a 7 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=8A9K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A9K FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DN:UNKNOWN+2-DEOXYNUCLEOTIDE'>DN</scene>, <scene name='pdbligand=JDA:5-methyl-2-(2-propan-2-ylphenyl)-~{N}-[[4-(1,2,3-triazol-1-yl)phenyl]methyl]pyrimidin-4-amine'>JDA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8a9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a9k OCA], [https://pdbe.org/8a9k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a9k RCSB], [https://www.ebi.ac.uk/pdbsum/8a9k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a9k ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UBP1_HUMAN UBP1_HUMAN] Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2 (PubMed:15694335). Also involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA (PubMed:16531995, PubMed:20147293). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity (PubMed:18082604, PubMed:26388029).<ref>PMID:15694335</ref> <ref>PMID:16531995</ref> <ref>PMID:18082604</ref> <ref>PMID:20147293</ref> <ref>PMID:26388029</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase 1 clinical trials, have been established, their binding mode is unknown. Here, we use cryo-electron microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5-A resolution, with and without ML323, we find an unusual binding mode in which the inhibitor disrupts part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1.

Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.,Rennie ML, Arkinson C, Chaugule VK, Walden H Sci Adv. 2022 Sep 30;8(39):eabq6353. doi: 10.1126/sciadv.abq6353. Epub 2022 Sep , 28. PMID:36170365<ref>PMID:36170365</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8a9k" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thioesterase 3D structures|Thioesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Rennie ML]]
[[Category: Walden H]]