View source for 9fci


==USP1 bound to KSQ-4279 and ubiquitin conjugated to FANCD2 (focused refinement)==
<StructureSection load='9fci' size='340' side='right'caption='[[9fci]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fci]] is a 2 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=9FCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FCI 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]] 3.2&#8491;</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=9fci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fci OCA], [https://pdbe.org/9fci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fci RCSB], [https://www.ebi.ac.uk/pdbsum/9fci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fci 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 ==
DNA damage triggers cell signaling cascades that mediate repair. This signaling is frequently dysregulated in cancers. The proteins that mediate this signaling are potential targets for therapeutic intervention. Ubiquitin-specific protease 1 (USP1) is one such target, with small-molecule inhibitors already in clinical trials. Here, we use biochemical assays and cryo-electron microscopy (cryo-EM) to study the clinical USP1 inhibitor, KSQ-4279 (RO7623066), and compare this to the well-established tool compound, ML323. We find that KSQ-4279 binds to the same cryptic site of USP1 as ML323 but disrupts the protein structure in subtly different ways. Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.

Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.,Rennie ML, Gundogdu M, Arkinson C, Liness S, Frame S, Walden H J Med Chem. 2024 Aug 27. doi: 10.1021/acs.jmedchem.4c01184. PMID:39190802<ref>PMID:39190802</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fci" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gundogdu M]]
[[Category: Rennie ML]]
[[Category: Walden H]]