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Lookup NU author(s): Dr Ian HopeORCiD, Dr Mathew MartinORCiD, Dr Ziwei Jiang, Professor Mike WaringORCiD, Professor Martin NobleORCiD, Professor Jane EndicottORCiD, Dr Natalie TatumORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Sites of protein-protein interaction (PPI) are potentially more selective binding sites for therapeutics than protein substrate-binding sites. PPIs include distinct regions frequently called “hotspots,” sites of key amino acid interactions. Prospective identification of these hotspots through X-ray crystallographic screening could assist in the identification of separation of function mutants for experimental validation, enhance confidence in AI-generated multiprotein complex predictions, and accelerate development of selective chemical probes. To explore these applications, we utilize the FragLite library to examine the binding surfaces of CDK2-cyclin A. The many protein- and peptide-CDK2-cyclin A complexes that have been structurally characterized make this complex an appropriate test case. We show that FragLites comprehensively map both known sites of protein-protein interaction on CDK2-cyclin A and identify a possible uncharacterized site, providing a structural method toward directing mechanistic studies and starting points for chemical probe design.
Author(s): Hope I, Martin MP, Jiang Z, Waring MJ, Noble MEM, Endicott JA, Tatum NJ
Publication type: Article
Publication status: Published
Journal: Structure
Year: 2025
Pages: Epub ahead of print
Online publication date: 14/08/2025
Acceptance date: 20/07/2025
Date deposited: 06/10/2025
ISSN (print): 0969-2126
ISSN (electronic): 1878-4186
Publisher: Cell Press
URL: https://doi.org/10.1016/j.str.2025.07.016
DOI: 10.1016/j.str.2025.07.016
Data Access Statement: All crystallographic results have been deposited at the Protein DataBank (PDB) https://www.rcsb.org/ and are publicly available. Accession numbers are listed in the key resources table. PDB accession codes for structures used within, but not derived from, this study, CDK2 (PDB 1HCK), CDK2-cyclin A (PDB 6GUC), CDK2-cyclin A-p27 (PDB 1JSU), CDK2-KAP (PDB 1FPZ), CDK2-CKS1 (PDB 1BUH), and CDK2-cyclin A-CDC25A (PDB 8ROZ). This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
PubMed id: 40816275
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