3RE2
Crystal structure of menin reveals the binding site for Mixed Lineage Leukemia (MLL) protein
Summary for 3RE2
| Entry DOI | 10.2210/pdb3re2/pdb |
| Descriptor | Predicted protein, GLYCEROL (3 entities in total) |
| Functional Keywords | menin, multiple endocrine neoplasia 1, tumor suppressor, mixed lineage leukemia, unknown function |
| Biological source | Nematostella vectensis (Starlet sea anemone) |
| Total number of polymer chains | 1 |
| Total formula weight | 53090.08 |
| Authors | Murai, M.J.,Chruszcz, M.,Reddy, G.,Grembecka, J.,Cierpicki, T. (deposition date: 2011-04-02, release date: 2011-07-13, Last modification date: 2024-02-21) |
| Primary citation | Murai, M.J.,Chruszcz, M.,Reddy, G.,Grembecka, J.,Cierpicki, T. Crystal Structure of Menin Reveals Binding Site for Mixed Lineage Leukemia (MLL) Protein. J.Biol.Chem., 286:31742-31748, 2011 Cited by PubMed Abstract: Menin is a tumor suppressor protein that is encoded by the MEN1 (multiple endocrine neoplasia 1) gene and controls cell growth in endocrine tissues. Importantly, menin also serves as a critical oncogenic cofactor of MLL (mixed lineage leukemia) fusion proteins in acute leukemias. Direct association of menin with MLL fusion proteins is required for MLL fusion protein-mediated leukemogenesis in vivo, and this interaction has been validated as a new potential therapeutic target for development of novel anti-leukemia agents. Here, we report the first crystal structure of menin homolog from Nematostella vectensis. Due to a very high sequence similarity, the Nematostella menin is a close homolog of human menin, and these two proteins likely have very similar structures. Menin is predominantly an α-helical protein with the protein core comprising three tetratricopeptide motifs that are flanked by two α-helical bundles and covered by a β-sheet motif. A very interesting feature of menin structure is the presence of a large central cavity that is highly conserved between Nematostella and human menin. By employing site-directed mutagenesis, we have demonstrated that this cavity constitutes the binding site for MLL. Our data provide a structural basis for understanding the role of menin as a tumor suppressor protein and as an oncogenic co-factor of MLL fusion proteins. It also provides essential structural information for development of inhibitors targeting the menin-MLL interaction as a novel therapeutic strategy in MLL-related leukemias. PubMed: 21757704DOI: 10.1074/jbc.M111.258186 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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