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7kwa
From Proteopedia
(Difference between revisions)
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==Structure of DCN1 bound to N-((4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(trifluoromethyl)benzamide== | ==Structure of DCN1 bound to N-((4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(trifluoromethyl)benzamide== | ||
| - | <StructureSection load='7kwa' size='340' side='right'caption='[[7kwa]]' scene=''> | + | <StructureSection load='7kwa' size='340' side='right'caption='[[7kwa]], [[Resolution|resolution]] 1.57Å' 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=7KWA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KWA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7kwa]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterobacteria_phage_RB59 Enterobacteria phage RB59] 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=7KWA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KWA 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=7kwa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kwa OCA], [https://pdbe.org/7kwa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kwa RCSB], [https://www.ebi.ac.uk/pdbsum/7kwa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kwa 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]] 1.572Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YHP:N-[(4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-(trifluoromethyl)benzamide'>YHP</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=7kwa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kwa OCA], [https://pdbe.org/7kwa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kwa RCSB], [https://www.ebi.ac.uk/pdbsum/7kwa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kwa ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/A0A097J809_BPT4 A0A097J809_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 == | ||
| + | The cullin-RING ubiquitin ligases (CRLs) are ubiquitin E3 enzymes that play a key role in controlling proteasomal degradation and are activated by neddylation. We previously reported inhibitors that target CRL activation by disrupting the interaction of defective in cullin neddylation 1 (DCN1), a CRL neddylation co-E3, and UBE2M, a neddylation E2. Our first-generation inhibitors possessed poor oral bioavailability and fairly rapid clearance that hindered the study of acute inhibition of DCN-controlled CRL activity in vivo. Herein, we report studies to improve the pharmacokinetic performance of the pyrazolo-pyridone inhibitors. The current best inhibitor, 40, inhibits the interaction of DCN1 and UBE2M, blocks NEDD8 transfer in biochemical assays, thermally stabilizes cellular DCN1, and inhibits anchorage-independent growth in a DCN1 amplified squamous cell carcinoma cell line. Additionally, we demonstrate that a single oral 50 mg/kg dose sustains plasma exposures above the biochemical IC90 for 24 h in mice. | ||
| + | |||
| + | Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.,Kim HS, Hammill JT, Scott DC, Chen Y, Rice AL, Pistel W, Singh B, Schulman BA, Guy RK J Med Chem. 2021 May 13;64(9):5850-5862. doi: 10.1021/acs.jmedchem.1c00035. Epub , 2021 May 4. PMID:33945681<ref>PMID:33945681</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7kwa" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Enterobacteria phage RB59]] | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Guy RK]] | [[Category: Guy RK]] | ||
Current revision
Structure of DCN1 bound to N-((4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(trifluoromethyl)benzamide
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