4GQ6

Human menin in complex with MLL peptide

Summary for 4GQ6

• Entry DOI: 10.2210/pdb4gq6/pdb
• Related: 4GPQ 4GQ3 4GQ4
• Descriptor: Menin, Histone-lysine N-methyltransferase MLL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: tumor suppressor, nucleus, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: O00255; Nucleus. MLL cleavage product N320: Nucleus. MLL cleavage product C180: Nucleus: Q03164
• Total number of polymer chains: 2
• Total formula weight: 56739.57

Authors

Shi, A.,Murai, M.J.,He, S.,Lund, G.L.,Hartley, T.,Purohit, T.,Reddy, G.,Chruszcz, M.,Grembecka, J.,Cierpicki, T. (deposition date: 2012-08-22, release date: 2012-09-19, Last modification date: 2024-02-28)

Primary citation

Shi, A.,Murai, M.J.,He, S.,Lund, G.,Hartley, T.,Purohit, T.,Reddy, G.,Chruszcz, M.,Grembecka, J.,Cierpicki, T.
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia.
Blood, 120:4461-4469, 2012

PubMed Abstract: Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor.

PubMed: 22936661
DOI: 10.1182/blood-2012-05-429274

Experimental method

X-RAY DIFFRACTION (1.55 Å)