9o37: Difference between revisions
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The | ==The structure of PRMT4 in complex with YD1305== | ||
<StructureSection load='9o37' size='340' side='right'caption='[[9o37]], [[Resolution|resolution]] 2.11Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9o37]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9O37 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9O37 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1B7X:1-[2-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-[3-[[3-(4-chlorophenyl)phenyl]methylamino]propyl]amino]ethyl]-3-(phenylmethyl)urea'>A1B7X</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9o37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9o37 OCA], [https://pdbe.org/9o37 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9o37 RCSB], [https://www.ebi.ac.uk/pdbsum/9o37 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9o37 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CARM1_HUMAN CARM1_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.<ref>PMID:16497732</ref> <ref>PMID:19405910</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Protein 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<ref>PMID:42066234</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9o37" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bush M]] | |||
[[Category: Deng Y]] | |||
[[Category: Huang R]] | |||
[[Category: Noinaj N]] | |||
