4WOV

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH BMS-066 AKA 2-METHOXY-N-({6-[3-METHYL-7-(METHYLAMINO)-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0, 6]DODECA-1(9),2(6),4,7,11-PENTAEN-11-YL]PYRIDIN-2-YL}METHY L)ACETAMIDE

Summary for 4WOV

• Entry DOI: 10.2210/pdb4wov/pdb
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 2-methoxy-N-({6-[1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]pyridin-2-yl}methyl)acetamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, tyk2, pseudokinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72237.46

Authors

Muckelbauer, J.K. (deposition date: 2014-10-16, release date: 2015-03-18, Last modification date: 2023-12-27)

Primary citation

Tokarski, J.S.,Zupa-Fernandez, A.,Tredup, J.A.,Pike, K.,Chang, C.,Xie, D.,Cheng, L.,Pedicord, D.,Muckelbauer, J.,Johnson, S.R.,Wu, S.,Edavettal, S.C.,Hong, Y.,Witmer, M.R.,Elkin, L.L.,Blat, Y.,Pitts, W.J.,Weinstein, D.S.,Burke, J.R.
Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.
J.Biol.Chem., 290:11061-11074, 2015

PubMed Abstract: Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.

PubMed: 25762719
DOI: 10.1074/jbc.M114.619502

Experimental method

X-RAY DIFFRACTION (1.8 Å)