5M25

Modulation of MLL1 Methyltransferase Activity

Summary for 5M25

• Entry DOI: 10.2210/pdb5m25/pdb
• Descriptor: WD repeat-containing protein 5, (2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-azanyl-3-oxidanyl-propanoyl]amino]propanoyl]amino]-5-carbamimidamido-~{N}-[(2~{S})-1-[[4-[(~{E})-[4-(hydroxymethyl)phenyl]diazenyl]phenyl]methylamino]-1-oxidanylidene-propan-2-yl]pentanamide (3 entities in total)
• Functional Keywords: mll1 methyltransferase peptide complex wdr5, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P61964
• Total number of polymer chains: 1
• Total formula weight: 48739.01

Authors

Srinivasan, V. (deposition date: 2016-10-11, release date: 2017-06-28, Last modification date: 2024-01-17)

Primary citation

Albert, L.,Xu, J.,Wan, R.,Srinivasan, V.,Dou, Y.,Vazquez, O.
Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.
Chem Sci, 8:4612-4618, 2017

PubMed Abstract: We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein-protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity ( = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable and conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein-protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states.

PubMed: 28970883
DOI: 10.1039/c7sc00137a

Experimental method

X-RAY DIFFRACTION (2.43 Å)