6xoq: Difference between revisions
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==DCN1 covalently bound to inhibitor 4== | ==DCN1 covalently bound to inhibitor 4== | ||
<StructureSection load='6xoq' size='340' side='right'caption='[[6xoq]]' scene=''> | <StructureSection load='6xoq' size='340' side='right'caption='[[6xoq]], [[Resolution|resolution]] 2.07Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XOQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XOQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[6xoq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XOQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XOQ FirstGlance]. <br> | ||
</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=6xoq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xoq OCA], [https://pdbe.org/6xoq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xoq RCSB], [https://www.ebi.ac.uk/pdbsum/6xoq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xoq ProSAT]</span></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]] 2.07Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H9S:(2E)-N-[(2S)-2-cyclohexyl-2-({N-propanoyl-3-[6-(propan-2-yl)-1,3-benzothiazol-2-yl]-L-alanyl}amino)ethyl]-4-(morpholin-4-yl)but-2-enamide'>H9S</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=6xoq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xoq OCA], [https://pdbe.org/6xoq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xoq RCSB], [https://www.ebi.ac.uk/pdbsum/6xoq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xoq ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/D9IEF7_BPT4 D9IEF7_BPT4] [https://www.uniprot.org/uniprot/DCNL1_HUMAN DCNL1_HUMAN] Part of an E3 ubiquitin ligase complex for neddylation. Required for neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes by enhancing the rate of cullins neddylation. Functions to recruit the NEDD8-charged E2 enzyme to the cullin component. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity. Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation. | |||
Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity.,Zhou H, Lu J, Chinnaswamy K, Stuckey JA, Liu L, McEachern D, Yang CY, Bernard D, Shen H, Rui L, Sun Y, Wang S Nat Commun. 2021 May 11;12(1):2621. doi: 10.1038/s41467-021-22924-4. PMID:33976147<ref>PMID:33976147</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6xoq" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Escherichia virus T4]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Stuckey JA]] | [[Category: Stuckey JA]] | ||
Latest revision as of 17:58, 18 October 2023
DCN1 covalently bound to inhibitor 4DCN1 covalently bound to inhibitor 4
Structural highlights
FunctionD9IEF7_BPT4 DCNL1_HUMAN Part of an E3 ubiquitin ligase complex for neddylation. Required for neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes by enhancing the rate of cullins neddylation. Functions to recruit the NEDD8-charged E2 enzyme to the cullin component. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity. Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity). Publication Abstract from PubMedCullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation. Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity.,Zhou H, Lu J, Chinnaswamy K, Stuckey JA, Liu L, McEachern D, Yang CY, Bernard D, Shen H, Rui L, Sun Y, Wang S Nat Commun. 2021 May 11;12(1):2621. doi: 10.1038/s41467-021-22924-4. PMID:33976147[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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