2MTN

Solution structure of MLL-IBD complex

2MTN の概要

• エントリーDOI: 10.2210/pdb2mtn/pdb
• NMR情報: BMRB: 25171
• 分子名称: Histone-lysine N-methyltransferase 2A, PC4 and SFRS1-interacting protein fusion (1 entity in total)
• 機能のキーワード: protein-protein complex, transferase-protein binding complex, transferase/protein binding
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : O75475
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18208.90

構造登録者

Cierpicki, T.,Pollock, J.,Murai, M. (登録日: 2014-08-23, 公開日: 2014-12-03, 最終更新日: 2024-05-01)

主引用文献

Murai, M.J.,Pollock, J.,He, S.,Miao, H.,Purohit, T.,Yokom, A.,Hess, J.L.,Muntean, A.G.,Grembecka, J.,Cierpicki, T.
The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV.
Blood, 124:3730-3737, 2014

PubMed Abstract: Lens epithelium-derived growth factor (LEDGF) is a chromatin-associated protein implicated in leukemia and HIV type 1 infection. LEDGF associates with mixed-lineage leukemia (MLL) fusion proteins and menin and is required for leukemic transformation. To better understand the molecular mechanism underlying the LEDGF integrase-binding domain (IBD) interaction with MLL fusion proteins in leukemia, we determined the solution structure of the MLL-IBD complex. We found a novel MLL motif, integrase domain binding motif 2 (IBM2), which binds to a well-defined site on IBD. Point mutations within IBM2 abolished leukemogenic transformation by MLL-AF9, validating that this newly identified motif is essential for the oncogenic activity of MLL fusion proteins. Interestingly, the IBM2 binding site on IBD overlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD from the menin-MLL complex. A short IBM2 peptide binds to IBD directly and inhibits both the IBD-MLL/menin and IBD-IN interactions. Our findings show that the same site on IBD is involved in binding to MLL and HIV-IN, revealing an attractive approach to simultaneously target LEDGF in leukemia and HIV.

PubMed: 25305204
DOI: 10.1182/blood-2014-01-550079

実験手法

SOLUTION NMR