6p5w
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of DCN1 bound to 3-methyl-N-((4S,5S)-3-methyl-6-oxo-1-phenyl-4-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide== | |
| + | <StructureSection load='6p5w' size='340' side='right'caption='[[6p5w]], [[Resolution|resolution]] 1.69Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6p5w]] 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=6P5W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P5W 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]] 1.69Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O0A:3-methyl-N-[(4S,5S)-3-methyl-4-(4-methylphenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl]benzamide'>O0A</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=6p5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5w OCA], [https://pdbe.org/6p5w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p5w RCSB], [https://www.ebi.ac.uk/pdbsum/6p5w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5w ProSAT]</span></td></tr> | ||
| + | </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 == | ||
| + | Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 25-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein-protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification. | ||
| - | + | Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation.,Kim HS, Hammill JT, Scott DC, Chen Y, Min J, Rector J, Singh B, Schulman BA, Guy RK J Med Chem. 2019 Sep 26;62(18):8429-8442. doi: 10.1021/acs.jmedchem.9b00410. Epub, 2019 Sep 13. PMID:31465221<ref>PMID:31465221</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6p5w" style="background-color:#fffaf0;"></div> |
| - | [[Category: Guy | + | == References == |
| - | [[Category: Kim | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| + | [[Category: Escherichia virus T4]] | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Guy RK]] | ||
| + | [[Category: Hammill JT]] | ||
| + | [[Category: Kim HS]] | ||
| + | [[Category: Schulman BA]] | ||
| + | [[Category: Scott DC]] | ||
Current revision
Structure of DCN1 bound to 3-methyl-N-((4S,5S)-3-methyl-6-oxo-1-phenyl-4-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide
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