6dud: Difference between revisions
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==JAK3 with cyanamide CP12== | |||
<StructureSection load='6dud' size='340' side='right'caption='[[6dud]], [[Resolution|resolution]] 1.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6dud]] 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=6DUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DUD 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]] 1.66Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HB4:~{N}-[(1~{S})-6-(7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1~{H}-inden-1-yl]methanimidamide'>HB4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6dud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dud OCA], [https://pdbe.org/6dud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dud RCSB], [https://www.ebi.ac.uk/pdbsum/6dud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dud ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors. | |||
Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors.,Casimiro-Garcia A, Trujillo JI, Vajdos F, Juba B, Banker ME, Aulabaugh A, Balbo P, Bauman J, Chrencik J, Coe JW, Czerwinski R, Dowty M, Knafels JD, Kwon S, Leung L, Liang S, Robinson RP, Telliez JB, Unwalla R, Yang X, Thorarensen A J Med Chem. 2018 Nov 30. doi: 10.1021/acs.jmedchem.8b01308. PMID:30423248<ref>PMID:30423248</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Vajdos | <div class="pdbe-citations 6dud" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Janus kinase 3D structures|Janus kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Vajdos FF]] | |||
