5v8n - Revision history

OCA: Redirecting to 6nao

2018-12-19T08:02:28Z

Redirecting to 6nao

←Older revision		Revision as of 08:02, 19 December 2018
Line 1:		Line 1:
-		+	#REDIRECT [[6nao]] This PDB entry is obsolete and replaced by 6nao
-	~~==Discovery of a high affinity inhibitor of cGAS==~~	+
-	~~<StructureSection load='5v8n' size='340' side='right' caption='~~[[~~5v8n~~]]~~, [[Resolution\|resolution]] 3.23Å' scene=''>~~	+
-	~~== Structural highlights ==~~	+
-	<table><tr><td colspan='2'>[[5v8n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V8N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V8N FirstGlance]. <br>	+
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8ZP:(1R,2S)-2-[(4-hydroxy-2-phenylpyrrolo[1,2-a]pyrimidine-8-carbonyl)amino]cyclohexane-1-carboxylic+acid'>8ZP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>	+
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5v8j\|5v8j]], [[5v8h\|5v8h]], [[5v8o\|5v8o]]</td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclic_GMP-AMP_synthase Cyclic GMP-AMP synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.86 2.7.7.86] </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=5v8n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v8n OCA], [http://pdbe.org/5v8n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v8n RCSB], [http://www.ebi.ac.uk/pdbsum/5v8n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v8n ProSAT]</span></td></tr>	+
-	~~</table>~~	+
-	~~== Function ==~~	+
-	[[http://www.uniprot.org/uniprot/CGAS_HUMAN CGAS_HUMAN]] Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production.<ref>PMID:21478870</ref> <ref>PMID:23258413</ref>	+
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is ~~a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound,~~ and ~~establish a high throughput assay for the identification of next generation cGAS inhibitors.~~	+
-		+
-	~~Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled~~ by a novel fluorescence polarization assay.,Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, Aulabaugh A, Aivazian D, Castro D, Chen M, Culp J, Dower K, Gardner J, Hawrylik S, Golenbock D, Hepworth D, Horn M, Jones L, Jones P, Latz E, Li J, Lin LL, Lin W, Lin D, Lovering F, Niljanskul N, Nistler R, Pierce B, Plotnikova O, Schmitt D, Shanker S, Smith J, Snyder W, Subashi T, Trujillo J, Tyminski E, Wang G, Wong J, Lefker B, Dakin L, Leach K PLoS One. 2017 Sep 21;12(9):e0184843. doi: 10.1371/journal.pone.0184843., eCollection 2017. PMID:28934246<ref>PMID:28934246</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5v8n" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references/>~~	+
-	~~__TOC__~~	+
-	~~</StructureSection>~~	+
-	~~[[Category: Cyclic GMP-AMP synthase]]~~	+
-	~~[[Category: Hall, J]]~~	+
-	~~[[Category: Cgamp]]~~	+
-	~~[[Category: Cga]]~~	+
-	~~[[Category: Sting]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex]]~~	+

OCA at 09:16, 4 October 2017

2017-10-04T09:16:20Z

←Older revision		Revision as of 09:16, 4 October 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5v8n is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Discovery of a high affinity inhibitor of cGAS==
		+	<StructureSection load='5v8n' size='340' side='right' caption='[[5v8n]], [[Resolution\|resolution]] 3.23Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5v8n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V8N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V8N FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8ZP:(1R,2S)-2-[(4-hydroxy-2-phenylpyrrolo[1,2-a]pyrimidine-8-carbonyl)amino]cyclohexane-1-carboxylic+acid'>8ZP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5v8j\|5v8j]], [[5v8h\|5v8h]], [[5v8o\|5v8o]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclic_GMP-AMP_synthase Cyclic GMP-AMP synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.86 2.7.7.86] </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=5v8n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v8n OCA], [http://pdbe.org/5v8n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v8n RCSB], [http://www.ebi.ac.uk/pdbsum/5v8n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v8n ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CGAS_HUMAN CGAS_HUMAN]] Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production.<ref>PMID:21478870</ref> <ref>PMID:23258413</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.

-	~~Authors:~~ Hall, J.	+	Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.,Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, Aulabaugh A, Aivazian D, Castro D, Chen M, Culp J, Dower K, Gardner J, Hawrylik S, Golenbock D, Hepworth D, Horn M, Jones L, Jones P, Latz E, Li J, Lin LL, Lin W, Lin D, Lovering F, Niljanskul N, Nistler R, Pierce B, Plotnikova O, Schmitt D, Shanker S, Smith J, Snyder W, Subashi T, Trujillo J, Tyminski E, Wang G, Wong J, Lefker B, Dakin L, Leach K PLoS One. 2017 Sep 21;12(9):e0184843. doi: 10.1371/journal.pone.0184843., eCollection 2017. PMID:28934246<ref>PMID:28934246</ref>

-	~~Description: Discovery of~~ a ~~high affinity inhibitor~~ of ~~cGAS~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5v8n" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Cyclic GMP-AMP synthase]]
	[[Category: Hall, J]]		[[Category: Hall, J]]
		+	[[Category: Cgamp]]
		+	[[Category: Cga]]
		+	[[Category: Sting]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 09:44, 12 April 2017

2017-04-12T09:44:15Z

←Older revision		Revision as of 09:44, 12 April 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5v8n is ON HOLD	+	The entry 5v8n is ON HOLD until Paper Publication

	Authors: Hall, J.		Authors: Hall, J.

OCA: Protected "5v8n" [edit=sysop:move=sysop]

2017-04-05T11:45:01Z

Protected "5v8n" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:45, 5 April 2017

OCA: New page: '''Unreleased structure''' The entry 5v8n is ON HOLD Authors: Hall, J. Description: Discovery of a high affinity inhibitor of cGAS Category: Unreleased Structures [[Category: Hall,...

2017-04-05T11:44:59Z

New page: '''Unreleased structure''' The entry 5v8n is ON HOLD Authors: Hall, J. Description: Discovery of a high affinity inhibitor of cGAS Category: Unreleased Structures [[Category: Hall,...

New page

'''Unreleased structure'''

The entry 5v8n is ON HOLD

Authors: Hall, J.

Description: Discovery of a high affinity inhibitor of cGAS
[[Category: Unreleased Structures]]
[[Category: Hall, J]]