7kwa - Revision history

OCA at 15:32, 18 October 2023

OCA — Wed, 18 Oct 2023 15:32:49 GMT

←Older revision		Revision as of 15:32, 18 October 2023
Line 1:		Line 1:

	==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]]

OCA at 09:54, 14 July 2021

OCA — Wed, 14 Jul 2021 09:54:12 GMT

←Older revision		Revision as of 09:54, 14 July 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 7kwa is ON HOLD until Paper Publication~~	+	==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=''>
-	~~Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C.~~	+	== 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>
-	~~Description:~~ 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	+	</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>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Scott~~, D.C]]	+	__TOC__
-	[[Category: ~~Guy, R.K~~]]	+	</StructureSection>
-	[[Category: ~~Kim, H.S~~]]	+	[[Category: Large Structures]]
-	[[Category: Hammill~~, J.T~~]]	+	[[Category: Guy RK]]
-	[[Category: Schulman~~, B.A~~]]	+	[[Category: Hammill JT]]
		+	[[Category: Kim HS]]
		+	[[Category: Schulman BA]]
		+	[[Category: Scott DC]]

OCA at 05:37, 14 April 2021

OCA — Wed, 14 Apr 2021 05:37:20 GMT

←Older revision		Revision as of 05:37, 14 April 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7kwa is ON HOLD	+	The entry 7kwa is ON HOLD until Paper Publication

	Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C.		Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C.

OCA: Protected "7kwa" [edit=sysop:move=sysop]

OCA — Wed, 09 Dec 2020 05:16:29 GMT

Protected "7kwa" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:16, 9 December 2020

OCA: New page: '''Unreleased structure''' The entry 7kwa is ON HOLD Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C. Description: Structure of DCN1 bound to N-((4S,5S)-3-(ami...

OCA — Wed, 09 Dec 2020 05:16:28 GMT

New page: '''Unreleased structure''' The entry 7kwa is ON HOLD Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C. Description: Structure of DCN1 bound to N-((4S,5S)-3-(ami...

New page

'''Unreleased structure'''

The entry 7kwa is ON HOLD

Authors: Kim, H.S., Hammill, J.T., Schulman, B.A., Guy, R.K., Scott, D.C.

Description: 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
[[Category: Unreleased Structures]]
[[Category: Scott, D.C]]
[[Category: Guy, R.K]]
[[Category: Kim, H.S]]
[[Category: Hammill, J.T]]
[[Category: Schulman, B.A]]