View source for 9o6h


==The Structure of PRMT4 in complex with SGC8172==
<StructureSection load='9o6h' size='340' side='right'caption='[[9o6h]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9o6h]] is a 4 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=9O6H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9O6H 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]] 1.97&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1B9W:(2~{R},3~{R},4~{S},5~{S})-2-(6-aminopurin-9-yl)-5-[3-[[3-(4-chlorophenyl)phenyl]methylamino]propylsulfanylmethyl]oxolane-3,4-diol'>A1B9W</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=9o6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9o6h OCA], [https://pdbe.org/9o6h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9o6h RCSB], [https://www.ebi.ac.uk/pdbsum/9o6h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9o6h 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) &lt;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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9o6h" 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]]