9C4S

Menin mutant G331R in complex with MLL peptide

Summary for 9C4S

• Entry DOI: 10.2210/pdb9c4s/pdb
• Descriptor: Menin, MLL cleavage product N320, SULFATE ION, ... (7 entities in total)
• Functional Keywords: protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 56807.69

Authors

Clegg, B.D.,Cierpicki, T.,Grembecka, J. (deposition date: 2024-06-05, release date: 2025-05-21, Last modification date: 2025-12-24)

Primary citation

Ray, J.,Clegg, B.,Grembecka, J.,Cierpicki, T.
Drug-resistant menin variants retain high binding affinity and interactions with MLL1.
J.Biol.Chem., 300:107777-107777, 2024

PubMed Abstract: Menin is an essential oncogenic cofactor of MLL1 fusion proteins in acute leukemias and inhibitors of the menin-MLL1 interaction are under evaluation in clinical trials. Recent studies found emerging resistance to menin inhibitor treatment in patients with leukemia as a result of somatic mutations in menin. To understand how patient mutations in menin affect the interaction with MLL1, we performed systematic characterization of the binding affinity of these menin mutants (T349M, M327I, G331R and G331D) and the N-terminal fragment of MLL1. We also determined the crystal structures of menin patient mutants and their complexes with MLL1-derived peptides. We found that drug-resistant mutations in menin occur at a site adjacent to the MLL1 binding site, but they do not affect MLL1 binding to menin. On the contrary, our structural analysis shows that all these point mutations in menin generate steric clash with menin inhibitors. We also found that mutation G331D results in a very slow dissociation of MLL1 from menin and this mutant might be particularly difficult to inhibit with small molecule drugs. This work provides structural information to support the development of a new generation of small molecule inhibitors that overcome resistance caused by menin mutations.

PubMed: 39276940
DOI: 10.1016/j.jbc.2024.107777

Experimental method

X-RAY DIFFRACTION (1.54 Å)