8a9k | pdb_00008a9k

Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 (consensus reconstruction)

Structural highlights

8a9k is a 7 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.85Å
Ligands:	DN, JDA, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[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:https://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:https://dx.doi.org/10.1016/j.str.2015.08.010
↑ Rennie ML, Arkinson C, Chaugule VK, Walden H. Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Sci Adv. 2022 Sep 30;8(39):eabq6353. PMID:36170365 doi:10.1126/sciadv.abq6353

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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:https://dx.doi.org/10.1016/j.molcel.2007.09.031

[4] 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

[5] 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:https://dx.doi.org/10.1016/j.str.2015.08.010

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

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8a9k | pdb_00008a9k

Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 (consensus reconstruction)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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