6bg5: Difference between revisions
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==Structure of 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-propylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)urea bound to DCN1== | |||
<StructureSection load='6bg5' size='340' side='right' caption='[[6bg5]], [[Resolution|resolution]] 1.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6bg5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BG5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BG5 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DQD:N-[(2H-1,3-benzodioxol-5-yl)methyl]-N-(1-propylpiperidin-4-yl)-N-[3-(trifluoromethyl)phenyl]urea'>DQD</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bg5 OCA], [http://pdbe.org/6bg5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bg5 RCSB], [http://www.ebi.ac.uk/pdbsum/6bg5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bg5 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4]] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers. | |||
Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation.,Hammill JT, Scott DC, Min J, Connelly MC, Holbrook G, Zhu F, Matheny A, Yang L, Singh B, Schulman BA, Guy RK J Med Chem. 2018 Apr 12;61(7):2680-2693. doi: 10.1021/acs.jmedchem.7b01277. Epub , 2018 Mar 26. PMID:29547696<ref>PMID:29547696</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Scott, D | <div class="pdbe-citations 6bg5" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Lysozyme]] | |||
[[Category: Guy, R K]] | |||
[[Category: Hammill, J T]] | |||
[[Category: Schulman, B A]] | |||
[[Category: Scott, D C]] | |||
[[Category: E3 ligase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Ligase-inhibitor complex]] | |||
Revision as of 11:01, 26 September 2018
Structure of 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-propylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)urea bound to DCN1Structure of 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-propylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)urea bound to DCN1
Structural highlights
Function[ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] Publication Abstract from PubMedWe previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers. Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation.,Hammill JT, Scott DC, Min J, Connelly MC, Holbrook G, Zhu F, Matheny A, Yang L, Singh B, Schulman BA, Guy RK J Med Chem. 2018 Apr 12;61(7):2680-2693. doi: 10.1021/acs.jmedchem.7b01277. Epub , 2018 Mar 26. PMID:29547696[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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