5k8v

Crystal Structure of Mus musculus Protein Arginine Methyltransferase 4 (CARM1 130-487) with CP1

spinqualitylabelsall models 5k8v, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5k8v is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: 6RE, DXE, EDO, PEG, PG6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CARM1_MOUSE 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 activates 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. Publication Abstract from PubMed PRMT2 is the less-characterized member of the protein arginine methyltransferase family in terms of structure, activity, and cellular functions. PRMT2 is a modular protein containing a catalytic Ado-Met-binding domain and unique Src homology 3 domain that binds proteins with proline-rich motifs. PRMT2 is involved in a variety of cellular processes and has diverse roles in transcriptional regulation through different mechanisms depending on its binding partners. PRMT2 has been demonstrated to have weak methyltransferase activity on a histone H4 substrate, but its optimal substrates have not yet been identified. To obtain insights into the function and activity of PRMT2, we solve several crystal structures of PRMT2 from two homologs (zebrafish and mouse) in complex with either the methylation product S-adenosyl-L-homocysteine or other compounds including the first synthetic PRMT2 inhibitor (Cp1) studied so far. We reveal that the N-terminal-containing SH3 module is disordered in the full-length crystal structures, and highlights idiosyncratic features of the PRMT2 active site. We identify a new nonhistone protein substrate belonging to the serine-/arginine-rich protein family which interacts with PRMT2 and we characterize six methylation sites by mass spectrometry. To better understand structural basis for Cp1 binding, we also solve the structure of the complex PRMT4:Cp1. We compare the inhibitor-protein interactions occurring in the PRMT2 and PRMT4 complex crystal structures and show that this compound inhibits efficiently PRMT2. These results are a first step toward a better understanding of PRMT2 substrate recognition and may accelerate the development of structure-based drug design of PRMT2 inhibitors. DATABASE: All coordinates and structure factors have been deposited in the Protein Data Bank: zPRMT21-408 -SFG = 5g02; zPRMT273-408 -SAH = 5fub; mPRMT21-445 -SAH = 5ful; mPRMT21-445 -Cp1 = 5fwa, mCARM1130-487 -Cp1 = 5k8v. Structural studies of protein arginine methyltransferase 2 reveal its interactions with potential substrates and inhibitors.,Cura V, Marechal N, Troffer-Charlier N, Strub JM, van Haren MJ, Martin NI, Cianferani S, Bonnefond L, Cavarelli J FEBS J. 2016 Nov 5. doi: 10.1111/febs.13953. PMID:27879050 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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