9DHK

RMI1-RMI2 bound to cyclic peptide L3

Summary for 9DHK

• Entry DOI: 10.2210/pdb9dhk/pdb
• Descriptor: RecQ-mediated genome instability protein 1, RecQ-mediated genome instability protein 2, L3 peptide, ... (7 entities in total)
• Functional Keywords: dna damage repair, complex, cyclic peptide, competitive inhibitor, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 135955.42

Authors

Bythell-Douglas, R.,Lau, Y.,Alcock, L.J.,Patel, K.,Gao, T.,Deshpande, C. (deposition date: 2024-09-03, 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

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: 40479515
DOI: 10.1021/acs.jmedchem.5c00365

Experimental method

X-RAY DIFFRACTION (2.35 Å)