4GM8

Crystal structure of human WD repeat domain 5 with compound MM-102

Summary for 4GM8

• Entry DOI: 10.2210/pdb4gm8/pdb
• Related: 4GM3 4GM9 4GMB
• Related PRD ID: PRD_000894
• Descriptor: WD repeat-containing protein 5, MM-102 (3 entities in total)
• Functional Keywords: mll1, histone methyltransferase, wd40, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P61964
• Total number of polymer chains: 8
• Total formula weight: 140247.22

Authors

Karatas, H.,Townsend, E.C.,Chen, Y.,Bernard, D.,Cao, F.,Liu, L.,Lei, M.,Dou, Y.,Wang, S. (deposition date: 2012-08-15, release date: 2013-07-31, Last modification date: 2024-10-09)

Primary citation

Karatas, H.,Townsend, E.C.,Cao, F.,Chen, Y.,Bernard, D.,Liu, L.,Lei, M.,Dou, Y.,Wang, S.
High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
J.Am.Chem.Soc., 135:669-682, 2013

PubMed Abstract: Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.

PubMed: 23210835
DOI: 10.1021/ja306028q

Experimental method

X-RAY DIFFRACTION (2.601 Å)