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4JLG

SETD7 in complex with inhibitor (R)-PFI-2 and S-adenosyl-methionine

Summary for 4JLG
Entry DOI10.2210/pdb4jlg/pdb
DescriptorHistone-lysine N-methyltransferase SETD7, S-ADENOSYLMETHIONINE, 8-fluoro-N-{(2R)-1-oxo-1-(pyrrolidin-1-yl)-3-[3-(trifluoromethyl)phenyl]propan-2-yl}-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide, ... (5 entities in total)
Functional Keywordsmethyltransferase, set domain, histone modification, transcription regulation, histone lysine methyltransferase, inhibitor, s-adenosyl-l-methionine, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationNucleus: Q8WTS6
Total number of polymer chains2
Total formula weight61163.82
Authors
Primary citationBarsyte-Lovejoy, D.,Li, F.,Oudhoff, M.J.,Tatlock, J.H.,Dong, A.,Zeng, H.,Wu, H.,Freeman, S.A.,Schapira, M.,Senisterra, G.A.,Kuznetsova, E.,Marcellus, R.,Allali-Hassani, A.,Kennedy, S.,Lambert, J.P.,Couzens, A.L.,Aman, A.,Gingras, A.C.,Al-Awar, R.,Fish, P.V.,Gerstenberger, B.S.,Roberts, L.,Benn, C.L.,Grimley, R.L.,Braam, M.J.,Rossi, F.M.,Sudol, M.,Brown, P.J.,Bunnage, M.E.,Owen, D.R.,Zaph, C.,Vedadi, M.,Arrowsmith, C.H.
(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells.
Proc.Natl.Acad.Sci.USA, 111:12853-12858, 2014
Cited by
PubMed Abstract: SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Ki (app) = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.
PubMed: 25136132
DOI: 10.1073/pnas.1407358111
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.896 Å)
Structure validation

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