View source for 7kib


==PRMT5:MEP50 Complexed with 5,5-Bicyclic Inhibitor Compound 4==
<StructureSection load='7kib' size='340' side='right'caption='[[7kib]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kib]] is a 2 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=7KIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KIB 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]] 2.52&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=WFM:(2~{R},3~{R},3~{a}~{S},6~{S},6~{a}~{R})-6-(2-azanyl-3-bromanyl-quinolin-7-yl)oxy-2-(4-azanylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6~{a}-hexahydrocyclopenta[b]furan-3,3~{a}-diol'>WFM</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=7kib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kib OCA], [https://pdbe.org/7kib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kib RCSB], [https://www.ebi.ac.uk/pdbsum/7kib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kib ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MEP50_HUMAN MEP50_HUMAN] Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage.<ref>PMID:11756452</ref> <ref>PMID:23071334</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.,Quiroz RV, Reutershan MH, Schneider SE, Sloman D, Lacey BM, Swalm BM, Yeung CS, Gibeau C, Spellman DS, Rankic DA, Chen D, Witter D, Linn D, Munsell E, Feng G, Xu H, Hughes JME, Lim J, Sauri J, Geddes K, Wan M, Mansueto MS, Follmer NE, Fier PS, Siliphaivanh P, Daublain P, Palte RL, Hayes RP, Lee S, Kawamura S, Silverman S, Sanyal S, Henderson TJ, Ye Y, Gao Y, Nicholson B, Machacek MR J Med Chem. 2021 Apr 8;64(7):3911-3939. doi: 10.1021/acs.jmedchem.0c02083. Epub , 2021 Mar 23. PMID:33755451<ref>PMID:33755451</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7kib" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hayes RP]]
[[Category: Palte RL]]