OCA at 12:41, 26 July 2023

2023-07-26T12:41:40Z

←Older revision		Revision as of 12:41, 26 July 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8s98 is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of the TYK2 pseudokinase domain in complex with compound 8==
		+	<StructureSection load='8s98' size='340' side='right'caption='[[8s98]], [[Resolution\|resolution]] 1.87Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8s98]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8S98 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8S98 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]] 1.87Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=ZRU:(8S)-N-cyclopropyl-5-[(2-methoxypyridin-3-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide'>ZRU</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=8s98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8s98 OCA], [https://pdbe.org/8s98 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8s98 RCSB], [https://www.ebi.ac.uk/pdbsum/8s98 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8s98 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:[https://omim.org/entry/611521 611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.

-	~~Authors~~: ~~Toms, A.V~~., Leit, S., Greenwood, J~~.R.~~, Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles~~, N.~~, Cartwright, M., Collis, A., Feng, S., Ghanakota, P., Harriman~~, G.C.~~, Hosagrahara, V., Kaila, N., Kapeller, R., Rafi~~, S.~~, Romero~~, D.L.~~, Tarantino~~, P.~~, Timaniya, J., Wester~~, R.T.~~, Westlin, W., Srivastava, B., Miao, W., Tummino, P., McElwee, J.J.~~, Edmondson, S~~.D.~~, Massee, C~~.E.	+	Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.,Leit S, Greenwood J, Carriero S, Mondal S, Abel R, Ashwell M, Blanchette H, Boyles NA, Cartwright M, Collis A, Feng S, Ghanakota P, Harriman GC, Hosagrahara V, Kaila N, Kapeller R, Rafi SB, Romero DL, Tarantino PM, Timaniya J, Toms AV, Wester RT, Westlin W, Srivastava B, Miao W, Tummino P, McElwee JJ, Edmondson SD, Masse CE J Med Chem. 2023 Jul 10. doi: 10.1021/acs.jmedchem.3c00600. PMID:37427891<ref>PMID:37427891</ref>

-	~~Description: Crystal structure~~ of the ~~TYK2 pseudokinase domain in complex with compound 8~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Leit, S~~]]	+	<div class="pdbe-citations 8s98" style="background-color:#fffaf0;"></div>
-	[[Category: Ashwell, M]]	+	== References ==
-	[[Category: ~~Kaila, N~~]]	+	<references/>
-	[[Category: ~~Timaniya, J~~]]	+	__TOC__
-	[[Category: ~~Mondal,~~ S]]	+	</StructureSection>
-	[[Category: ~~Rafi, S~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Feng, S~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Miao, W~~]]	+	[[Category: Abel R]]
-	[[Category: ~~Hosagrahara, V~~]]	+	[[Category: Ashwell M]]
-	[[Category: ~~Boyles, N~~]]	+	[[Category: Blanchette H]]
-	[[Category: ~~Toms, A.V~~]]	+	[[Category: Boyles N]]
-	[[Category: ~~Blanchette, H~~]]	+	[[Category: Carriero S]]
-	[[Category: ~~Abel, R~~]]	+	[[Category: Cartwright M]]
-	[[Category: ~~Harriman, G.C~~]]	+	[[Category: Collis A]]
-	[[Category: ~~Ghanakota, P~~]]	+	[[Category: Edmondson SD]]
-	[[Category: ~~Tarantino, P~~]]	+	[[Category: Feng S]]
-	[[Category: ~~Mcelwee, J.J~~]]	+	[[Category: Ghanakota P]]
-	[[Category: ~~Wester, R.T~~]]	+	[[Category: Greenwood JR]]
-	[[Category: ~~Tummino, P~~]]	+	[[Category: Harriman GC]]
-	[[Category: ~~Collis, A~~]]	+	[[Category: Hosagrahara V]]
-	[[Category: ~~Edmondson,~~ S.D]]	+	[[Category: Kaila N]]
-	[[Category: ~~Greenwood, J.R~~]]	+	[[Category: Kapeller R]]
-	[[Category: ~~Cartwright, M~~]]	+	[[Category: Leit S]]
-	[[Category: ~~Westlin, W~~]]	+	[[Category: Massee CE]]
-	[[Category: ~~Romero, D.L~~]]	+	[[Category: McElwee JJ]]
-	[[Category: ~~Massee, C.E~~]]	+	[[Category: Miao W]]
-	[[Category: ~~Srivastava, B~~]]	+	[[Category: Mondal S]]
-	[[Category: ~~Carriero, S~~]]	+	[[Category: Rafi S]]
-	[[Category: ~~Kapeller, R~~]]	+	[[Category: Romero DL]]
		+	[[Category: Srivastava B]]
		+	[[Category: Tarantino P]]
		+	[[Category: Timaniya J]]
		+	[[Category: Toms AV]]
		+	[[Category: Tummino P]]
		+	[[Category: Wester RT]]
		+	[[Category: Westlin W]]

OCA at 05:50, 3 May 2023

2023-05-03T05:50:49Z

←Older revision		Revision as of 05:50, 3 May 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8s98 is ON HOLD	+	The entry 8s98 is ON HOLD until Paper Publication

	Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwright, M., Collis, A., Feng, S., Ghanakota, P., Harriman, G.C., Hosagrahara, V., Kaila, N., Kapeller, R., Rafi, S., Romero, D.L., Tarantino, P., Timaniya, J., Wester, R.T., Westlin, W., Srivastava, B., Miao, W., Tummino, P., McElwee, J.J., Edmondson, S.D., Massee, C.E.		Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwright, M., Collis, A., Feng, S., Ghanakota, P., Harriman, G.C., Hosagrahara, V., Kaila, N., Kapeller, R., Rafi, S., Romero, D.L., Tarantino, P., Timaniya, J., Wester, R.T., Westlin, W., Srivastava, B., Miao, W., Tummino, P., McElwee, J.J., Edmondson, S.D., Massee, C.E.

OCA: Protected "8s98" [edit=sysop:move=sysop]

2023-04-07T05:14:51Z

Protected "8s98" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:14, 7 April 2023

OCA: New page: '''Unreleased structure''' The entry 8s98 is ON HOLD Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwri...

2023-04-07T05:14:49Z

New page: '''Unreleased structure''' The entry 8s98 is ON HOLD Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwri...

New page

'''Unreleased structure'''

The entry 8s98 is ON HOLD

Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwright, M., Collis, A., Feng, S., Ghanakota, P., Harriman, G.C., Hosagrahara, V., Kaila, N., Kapeller, R., Rafi, S., Romero, D.L., Tarantino, P., Timaniya, J., Wester, R.T., Westlin, W., Srivastava, B., Miao, W., Tummino, P., McElwee, J.J., Edmondson, S.D., Massee, C.E.

Description: Crystal structure of the TYK2 pseudokinase domain in complex with compound 8
[[Category: Unreleased Structures]]
[[Category: Leit, S]]
[[Category: Ashwell, M]]
[[Category: Kaila, N]]
[[Category: Timaniya, J]]
[[Category: Mondal, S]]
[[Category: Rafi, S]]
[[Category: Feng, S]]
[[Category: Miao, W]]
[[Category: Hosagrahara, V]]
[[Category: Boyles, N]]
[[Category: Toms, A.V]]
[[Category: Blanchette, H]]
[[Category: Abel, R]]
[[Category: Harriman, G.C]]
[[Category: Ghanakota, P]]
[[Category: Tarantino, P]]
[[Category: Mcelwee, J.J]]
[[Category: Wester, R.T]]
[[Category: Tummino, P]]
[[Category: Collis, A]]
[[Category: Edmondson, S.D]]
[[Category: Greenwood, J.R]]
[[Category: Cartwright, M]]
[[Category: Westlin, W]]
[[Category: Romero, D.L]]
[[Category: Massee, C.E]]
[[Category: Srivastava, B]]
[[Category: Carriero, S]]
[[Category: Kapeller, R]]

8s98 - Revision history

OCA at 12:41, 26 July 2023

OCA at 05:50, 3 May 2023

OCA: Protected "8s98" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8s98 is ON HOLD Authors: Toms, A.V., Leit, S., Greenwood, J.R., Carriero, S., Mondal, S., Abel, R., Ashwell, M., Blanchette, H., Boyles, N., Cartwri...