| Structural highlights
Function
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).[1] [2] [3] [4] [5]
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D'Andrea AD, Bernards R. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005 Feb 4;17(3):331-9. PMID:15694335 doi:10.1016/j.molcel.2005.01.008
- ↑ Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 2006 Apr;8(4):339-47. PMID:16531995 doi:10.1038/ncb1378
- ↑ Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007 Dec 14;28(5):786-97. PMID:18082604 doi:http://dx.doi.org/10.1016/j.molcel.2007.09.031
- ↑ Lee KY, Yang K, Cohn MA, Sikdar N, D'Andrea AD, Myung K. Human ELG1 regulates the level of ubiquitinated proliferating cell nuclear antigen (PCNA) through Its interactions with PCNA and USP1. J Biol Chem. 2010 Apr 2;285(14):10362-9. PMID:20147293 doi:10.1074/jbc.M109.092544
- ↑ Yin J, Schoeffler AJ, Wickliffe K, Newton K, Starovasnik MA, Dueber EC, Harris SF. Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46. Structure. 2015 Sep 12. pii: S0969-2126(15)00359-7. doi:, 10.1016/j.str.2015.08.010. PMID:26388029 doi:http://dx.doi.org/10.1016/j.str.2015.08.010
- ↑ Rennie ML, Gundogdu M, Arkinson C, Liness S, Frame S, Walden H. Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279. J Med Chem. 2024 Aug 27. PMID:39190802 doi:10.1021/acs.jmedchem.4c01184
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