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4gj3

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Revision as of 13:50, 4 August 2016

Tyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide

Structural highlights

4gj3 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4gih, 4gii, 4gj2, 4gvj
Gene:	Tyk2 (HUMAN)
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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: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

[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.^[1]

Publication Abstract from PubMed

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-gamma (IFNgamma), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors.,Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, Devoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29. PMID:23668484^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
↑ Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, Devoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S. Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors. J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29. PMID:23668484 doi:10.1021/jm400266t

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4gj3"

@@ Line 1: / Line 1: @@
 ==Tyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide==
 <StructureSection load='4gj3' size='340' side='right' caption='[[4gj3]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4gj3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GJ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GJ3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4gj3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GJ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GJ3 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0XP:2,6-DICHLORO-4-CYANO-N-[2-({[(1R,2R)-2-FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4-YL]BENZAMIDE'>0XP</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gih|4gih]], [[4gii|4gii]], [[4gj2|4gj2]], [[4gvj|4gvj]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4gj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gj3 RCSB], [http://www.ebi.ac.uk/pdbsum/4gj3 PDBsum]</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=4gj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj3 OCA], [http://pdbe.org/4gj3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gj3 RCSB], [http://www.ebi.ac.uk/pdbsum/4gj3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gj3 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4gj3" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 28: / Line 30: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Non-specific protein-tyrosine kinase]]
 [[Category: Ultsch, M H]]

4gj3

From Proteopedia

Revision as of 13:50, 4 August 2016

Tyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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