9DI4
RMI1-RMI2 bound to cyclic peptide L4
Summary for 9DI4
| Entry DOI | 10.2210/pdb9di4/pdb |
| Related | 9DHK |
| Descriptor | RecQ-mediated genome instability protein 1, RecQ-mediated genome instability protein 2, L4 cyclic peptide, ... (5 entities in total) |
| Functional Keywords | nuclear protein complex, genome stability, nuclear protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 34598.85 |
| Authors | Bythell-Douglas, R.,Lau, Y.H.,Alcock, L.J.,Gao, T.,Deshpande, C.,Patel, K. (deposition date: 2024-09-05, release date: 2025-07-02, Last modification date: 2025-07-09) |
| Primary citation | Alcock, L.J.,Gao, T.,Bythell-Douglas, R.,Gao, J.,Krishna Sudhakar, H.,Huang, T.,Young, R.,Vu, Q.N.,Deshpande, C.,Wilkinson-White, L.E.,Passioura, T.,Pickett, H.A.,Deans, A.J.,Lau, Y.H. Potent Cyclic Peptide Inhibitors Disrupt the FANCM-RMI Interaction. J.Med.Chem., 68:12615-12625, 2025 Cited by PubMed Abstract: FANCM-RMI is a protein-protein interaction that maintains genome stability during DNA repair events in cancers that rely on the Alternative Lengthening of Telomeres (ALT) pathway for survival. We report the first valid chemical inhibitors of the FANCM-RMI interaction discovered by screening cyclic peptides via mRNA display. These inhibitors engage the FANCM-binding pocket of RMI1/2 with nanomolar affinity ( = 2-10 nM) and are potent disruptors of the FANCM-RMI interaction (IC = 54-104 nM). X-ray crystallography and alanine scanning reveal novel binding modes and interactions between the cyclic peptides and RMI1/2 that drive high-potency inhibition. Co-immunoprecipitation studies confirm the complete disruption of the native interaction in whole osteosarcoma cell lysates. These inhibitors represent the first validated RMI binders toward developing chemical tools for interrogating the mechanistic roles of FANCM-RMI in mediating genome stability and provide a much-anticipated starting point to accelerate the development of FANCM-RMI inhibitors for intervention against ALT-driven cancers. PubMed: 40479515DOI: 10.1021/acs.jmedchem.5c00365 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.696 Å) |
Structure validation
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