2MSR

Solution structure of LEDGF/p75 IBD in complex with MLL1 peptide (140-160)

Summary for 2MSR

• Entry DOI: 10.2210/pdb2msr/pdb
• NMR Information: BMRB: 25130
• Descriptor: Histone-lysine N-methyltransferase 2A, PC4 and SFRS1-interacting protein (2 entities in total)
• Functional Keywords: ledgf/p75, mll, mixed lineage leukemia, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus. MLL cleavage product N320: Nucleus. MLL cleavage product C180: Nucleus: Q03164; Nucleus: O75475
• Total number of polymer chains: 2
• Total formula weight: 12532.30

Authors

Cermakova, K.,Tesina, P.,Demeulemeester, J.,El Ashkar, S.,Mereau, H.,Schwaller, J.,Rezacova, P.,Veverka, V.,De Rijck, J. (deposition date: 2014-08-05, release date: 2014-08-20, Last modification date: 2024-05-15)

Primary citation

Cermakova, K.,Tesina, P.,Demeulemeester, J.,El Ashkar, S.,Mereau, H.,Schwaller, J.,Rezacova, P.,Veverka, V.,De Rijck, J.
Validation and Structural Characterization of the LEDGF/p75-MLL Interface as a New Target for the Treatment of MLL-Dependent Leukemia.
Cancer Res., 74:5139-5151, 2014

PubMed Abstract: Mixed lineage leukemia (MLL) fusion-driven acute leukemias represent a genetically distinct subset of leukemias with poor prognosis. MLL forms a ternary complex with the lens epithelium-derived growth factor (LEDGF/p75) and MENIN. LEDGF/p75, a chromatin reader recognizing H3K36me3 marks, contributes to the association of the MLL multiprotein complex to chromatin. Formation of this complex is critical for the development of MLL leukemia. Available X-ray data represent only a partial structure of the LEDGF/p75-MLL-MENIN complex. Using nuclear magnetic resonance spectroscopy, we identified an additional LEDGF/p75-MLL interface, which overlaps with the binding site of known LEDGF/p75 interactors-HIV-1 integrase, PogZ, and JPO2. Binding of these proteins or MLL to LEDGF/p75 is mutually exclusive. The resolved structure, as well as mutational analysis, shows that the interaction is primarily sustained via two aromatic residues of MLL (F148 and F151). Colony-forming assays in MLL-AF9(+) leukemic cells expressing MLL interaction-defective LEDGF/p75 mutants revealed that this interaction is essential for transformation. Finally, we show that the clonogenic growth of primary murine MLL-AF9-expressing leukemic blasts is selectively impaired upon overexpression of a LEDGF/p75-binding cyclic peptide CP65, originally developed to inhibit the LEDGF/p75-HIV-1 integrase interaction. The newly defined protein-protein interface therefore represents a new target for the development of therapeutics against LEDGF/p75-dependent MLL fusion-driven leukemic disorders. Cancer Res; 74(18); 5139-51. ©2014 AACR.

PubMed: 25082813
DOI: 10.1158/0008-5472.CAN-13-3602

Experimental method

SOLUTION NMR