7un4: Difference between revisions

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-'''Unreleased structure'''
-The entry 7un4 is ON HOLD
+==Structure of MAP kinase phosphatase 5 in complex with 3,3-dimethyl-1-((9-propyl-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one, an allosteric inhibitor==
+<StructureSection load='7un4' size='340' side='right'caption='[[7un4]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7un4]] is a 6 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=7UN4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UN4 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]] 2.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NVF:1-{[(9aM)-5,6-dihydrothieno[2,3-h]quinazolin-2-yl]sulfanyl}-3,3-dimethylbutan-2-one'>NVF</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=7un4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7un4 OCA], [https://pdbe.org/7un4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7un4 RCSB], [https://www.ebi.ac.uk/pdbsum/7un4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7un4 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/DUS10_HUMAN DUS10_HUMAN] Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily.<ref>PMID:22375048</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)but an-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, the X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. We found that the parallel-displaced pi-pi interaction between the inhibitor three-ring core and Tyr435 is critical for modulating potency, and that modifications to the core and functionalization at the C-9 position are essential for ensuring proper positioning of the core for this interaction. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease.
-Authors:
+Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.,Gannam ZTK, Jamali H, Kweon OS, Herrington J, Shillingford SR, Papini C, Gentzel E, Lolis E, Bennett AM, Ellman JA, Anderson KS Eur J Med Chem. 2022 Sep 2;243:114712. doi: 10.1016/j.ejmech.2022.114712. PMID:36116232<ref>PMID:36116232</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7un4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[MAP kinase phosphatase|MAP kinase phosphatase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Anderson KS]]
+[[Category: Bennett AM]]
+[[Category: Ellman JA]]
+[[Category: Gannam ZTK]]
+[[Category: Jamali H]]
+[[Category: Lolis E]]