4GPQ
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
Summary for 4GPQ
| Entry DOI | 10.2210/pdb4gpq/pdb |
| Related | 4GQ3 4GQ4 4GQ6 |
| Descriptor | Menin, DI(HYDROXYETHYL)ETHER, TETRAETHYLENE GLYCOL, ... (5 entities in total) |
| Functional Keywords | tumor suppressor, nucleus, transcription |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus: O00255 |
| Total number of polymer chains | 1 |
| Total formula weight | 55214.99 |
| 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: 2012-08-21, release date: 2012-09-19, Last modification date: 2023-09-13) |
| 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 Cited by 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: 22936661DOI: 10.1182/blood-2012-05-429274 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.46 Å) |
Structure validation
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