6NM4

Crystal structure of SAM-bound PRDM9 in complex with MRK-740 inhibitor

Summary for 6NM4

• Entry DOI: 10.2210/pdb6nm4/pdb
• Descriptor: Histone-lysine N-methyltransferase PRDM9, ZINC ION, S-ADENOSYLMETHIONINE, ... (6 entities in total)
• Functional Keywords: pr set domain, lysine methyltransferase, inhibitor, structural genomics, structural genomics consortium, sgc, gene regulation-inhibitor complex, gene regulation/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 45461.52

Authors

Ivanochko, D.,Halabelian, L.,Fischer, C.,Sanders, J.M.,Kattar, S.D.,Brown, P.J.,Edwards, A.M.,Bountra, C.,Arrowsmith, C.H.,Structural Genomics Consortium (SGC) (deposition date: 2019-01-10, release date: 2019-02-13, Last modification date: 2023-10-11)

Primary citation

Allali-Hassani, A.,Szewczyk, M.M.,Ivanochko, D.,Organ, S.L.,Bok, J.,Ho, J.S.Y.,Gay, F.P.H.,Li, F.,Blazer, L.,Eram, M.S.,Halabelian, L.,Dilworth, D.,Luciani, G.M.,Lima-Fernandes, E.,Wu, Q.,Loppnau, P.,Palmer, N.,Talib, S.Z.A.,Brown, P.J.,Schapira, M.,Kaldis, P.,O'Hagan, R.C.,Guccione, E.,Barsyte-Lovejoy, D.,Arrowsmith, C.H.,Sanders, J.M.,Kattar, S.D.,Bennett, D.J.,Nicholson, B.,Vedadi, M.
Discovery of a chemical probe for PRDM9.
Nat Commun, 10:5759-5759, 2019

PubMed Abstract: PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

PubMed: 31848333
DOI: 10.1038/s41467-019-13652-x

Experimental method

X-RAY DIFFRACTION (2.58 Å)