9o6h | pdb_00009o6h
The Structure of PRMT4 in complex with SGC8172
Structural highlights
FunctionCARM1_HUMAN Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.[1] [2] Publication Abstract from PubMedProtein arginine methyltransferases (PRMTs) are appealing therapeutic targets due to their critical roles in regulating numerous cellular processes and their dysregulation in various diseases. Although SAH-based inhibitors effectively target PRMTs, achieving selectivity across different methyltransferases remains a significant challenge. Herein, we employed a hybrid strategy that incorporates optimal linker length and "T-shape" modifications to enhance inhibitor selectivity. Starting with a selective PRMT7 inhibitor SGC8158 (IC(50) <2.5 nM), we successfully transformed it into a selective PRMT4 inhibitor AK442 (IC(50) = 2.6 nM). This approach highlights the potential of these design strategies to tune inhibitor selectivity, facilitating the development of isoform-specific PRMT inhibitors from existing scaffolds. Tailoring PRMT Inhibition: Shifting PRMT7 Selectivity to PRMT4 through "T-Shape" Strategy and "Linker-Specific" Preferences.,Kulkarni AS, Deng Y, Nam HS, Zhao T, Masal DP, Bush MM, Noinaj N, Huang R J Med Chem. 2026 May 1. doi: 10.1021/acs.jmedchem.5c01782. PMID:42066234[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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