6CBY

Crystal structure of human SET and MYND Domain Containing protein 2 with MTF9975

Summary for 6CBY

• Entry DOI: 10.2210/pdb6cby/pdb
• Descriptor: N-lysine methyltransferase SMYD2, ZINC ION, [3-(4-amino-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)-3-methylazetidin-1-yl][1-({1-[(1R)-cyclohept-2-en-1-yl]piperidin-4-yl}methyl)-1H-pyrrol-3-yl]methanone, ... (4 entities in total)
• Functional Keywords: smyd2 mtf9975 inhibitor, structural genomics, structural genomics consortium, sgc, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : Q9NRG4
• Total number of polymer chains: 2
• Total formula weight: 101174.22

Authors

ZENG, H.,DONG, A.,Hutchinson, A.,Seitova, A.,TATLOCK, J.,KUMPF, R.,OWEN, A.,TAYLOR, A.,Casimiro-Garcia, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,BROWN, P.J.,WU, H.,Structural Genomics Consortium (SGC) (deposition date: 2018-02-05, release date: 2018-03-14, Last modification date: 2023-12-27)

Primary citation

Taylor, A.P.,Swewczyk, M.,Kennedy, S.,Trush, V.V.,Wu, H.,Zeng, H.,Dong, A.,Ferreira de Freitas, R.,Tatlock, J.,Kumpf, R.A.,Wythes, M.,Casimiro-Garcia, A.,Denny, R.A.,Parikh, M.D.,Li, F.,Barsyte-Lovejoy, D.,Schapira, M.,Vedadi, M.,Brown, P.J.,Arrowsmith, C.H.,Owen, D.R.
Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase.
J.Med.Chem., 62:7669-7683, 2019

PubMed Abstract: The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require -adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable.

PubMed: 31415173
DOI: 10.1021/acs.jmedchem.9b00112

Experimental method

X-RAY DIFFRACTION (2.55 Å)