This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

6nzr

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 08:28, 6 November 2019

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_12 AKA 4-[(2-methanesulfonylphenyl)amino]-N-(H3)methyl-6-[(pyridin-2- yl)amino]pyridazine-3-carboxamide

Structural highlights

6nzr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
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

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.,Wrobleski ST, Moslin R, Lin S, Zhang Y, Spergel S, Kempson J, Tokarski JS, Strnad J, Zupa-Fernandez A, Cheng L, Shuster D, Gillooly K, Yang X, Heimrich E, McIntyre KW, Chaudhry C, Khan J, Ruzanov M, Tredup J, Mulligan D, Xie D, Sun H, Huang C, D'Arienzo C, Aranibar N, Chiney M, Chimalakonda A, Pitts WJ, Lombardo L, Carter PH, Burke JR, Weinstein DS J Med Chem. 2019 Jul 18. doi: 10.1021/acs.jmedchem.9b00444. PMID:31318208^[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
↑ Wrobleski ST, Moslin R, Lin S, Zhang Y, Spergel S, Kempson J, Tokarski JS, Strnad J, Zupa-Fernandez A, Cheng L, Shuster D, Gillooly K, Yang X, Heimrich E, McIntyre KW, Chaudhry C, Khan J, Ruzanov M, Tredup J, Mulligan D, Xie D, Sun H, Huang C, D'Arienzo C, Aranibar N, Chiney M, Chimalakonda A, Pitts WJ, Lombardo L, Carter PH, Burke JR, Weinstein DS. Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. J Med Chem. 2019 Jul 18. doi: 10.1021/acs.jmedchem.9b00444. PMID:31318208 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00444

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6nzr"

@@ Line 3: / Line 3: @@
 <StructureSection load='6nzr' size='340' side='right'caption='[[6nzr]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6nzr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NZR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6nzr]] is a 2 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=6NZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NZR FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LAJ:N-methyl-4-{[2-(methylsulfonyl)phenyl]amino}-6-[(pyridin-2-yl)amino]pyridazine-3-carboxamide'>LAJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6nzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzr OCA], [http://pdbe.org/6nzr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nzr RCSB], [http://www.ebi.ac.uk/pdbsum/6nzr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzr ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Non-specific protein-tyrosine kinase]]

6nzr

From Proteopedia

Revision as of 08:28, 6 November 2019

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_12 AKA 4-[(2-methanesulfonylphenyl)amino]-N-(H3)methyl-6-[(pyridin-2- yl)amino]pyridazine-3-carboxamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox