8ppw
From Proteopedia
(Difference between revisions)
| (One intermediate revision not shown.) | |||
| Line 5: | Line 5: | ||
<table><tr><td colspan='2'>[[8ppw]] 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=8PPW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PPW FirstGlance]. <br> | <table><tr><td colspan='2'>[[8ppw]] 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=8PPW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PPW 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]] 1.53Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.53Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86F:(3~{S})- | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86F:methyl+(3~{S})-3-(pent-4-ynylcarbamoyl)pyrrolidine-1-carboximidothioate'>86F</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=8ppw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ppw OCA], [https://pdbe.org/8ppw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ppw RCSB], [https://www.ebi.ac.uk/pdbsum/8ppw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ppw ProSAT]</span></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=8ppw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ppw OCA], [https://pdbe.org/8ppw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ppw RCSB], [https://www.ebi.ac.uk/pdbsum/8ppw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ppw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| Line 14: | Line 14: | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| - | Cyanamides have emerged as privileged scaffolds in covalent inhibitors of deubiquitinating enzymes (DUBs). However, many compounds with a cyanopyrrolidine warhead show cross-reactivity toward small subsets of DUBs or toward the protein deglycase PARK7/DJ-1, hampering their use for the selective perturbation of a single DUB in living cells. Here, we disclose N'-alkyl,N-cyanopiperazines as structures for covalent enzyme inhibition with exceptional specificity for the DUB UCHL1 among 55 human deubiquitinases and with | + | Cyanamides have emerged as privileged scaffolds in covalent inhibitors of deubiquitinating enzymes (DUBs). However, many compounds with a cyanopyrrolidine warhead show cross-reactivity toward small subsets of DUBs or toward the protein deglycase PARK7/DJ-1, hampering their use for the selective perturbation of a single DUB in living cells. Here, we disclose N'-alkyl,N-cyanopiperazines as structures for covalent enzyme inhibition with exceptional specificity for the DUB UCHL1 among 55 human deubiquitinases and with effective target engagement in cells. Notably, transitioning from 5-membered pyrrolidines to 6-membered heterocycles eliminated PARK7 binding and introduced context-dependent reversibility of the isothiourea linkage to the catalytic cysteine of UCHL1. Compound potency and specificity were analysed by a range of biochemical assays and with a crystal structure of a cyanopiperazine in covalent complex with UCHL1. The structure revealed a compound-induced conformational restriction of the cross-over loop, which underlies the observed inhibitory potencies. Through the rationalization of specificities of different cyanamides, we introduce a framework for the investigation of protein reactivity of bioactive nitriles of this compound class. Our results represent an encouraging case study for the refining of electrophilic compounds into chemical probes, emphasizing the potential to engineer specificity through subtle chemical modifications around the warhead. |
| - | N-Cyanopiperazines as Specific Covalent Inhibitors of the Deubiquitinating Enzyme UCHL1.,Schmidt M, Grethe C, Recknagel S, Kipka GM, Klink N, Gersch M Angew Chem Int Ed Engl. 2024 | + | N-Cyanopiperazines as Specific Covalent Inhibitors of the Deubiquitinating Enzyme UCHL1.,Schmidt M, Grethe C, Recknagel S, Kipka GM, Klink N, Gersch M Angew Chem Int Ed Engl. 2024 Mar 18;63(12):e202318849. doi: , 10.1002/anie.202318849. Epub 2024 Feb 9. PMID:38239128<ref>PMID:38239128</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Structure of human PARK7 in complex with GK16S
| |||||||||||
