9fci: Difference between revisions
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New page: '''Unreleased structure''' The entry 9fci is ON HOLD Authors: Rennie, M.L., Gundogdu, M., Walden, H. Description: USP1 bound to KSQ-4279 and ubiquitin conjugated to FANCD2 (focused ref... |
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The | ==USP1 bound to KSQ-4279 and ubiquitin conjugated to FANCD2 (focused refinement)== | ||
<StructureSection load='9fci' size='340' side='right'caption='[[9fci]], [[Resolution|resolution]] 3.20Å' 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]] 3.2Å</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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 9fci" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Walden | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gundogdu M]] | |||
[[Category: Rennie ML]] | |||
[[Category: Walden H]] | |||
