PDBsum entry 3lxn

Transferase

PDB id: 3lxn

Contents

Protein chain

288 a.a. *

Ligands

MI1

Waters ×88

* Residue conservation analysis

PDB id:

3lxn

Name:

Transferase

Title:

Structural and thermodynamic characterization of the tyk2 and jak3 kinase domains in complex with cp-690550 and cmp-6

Structure:

Non-receptor tyrosine-protein kinase tyk2. Chain: a. Fragment: kinase domain. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tyk2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.50Å R-factor: 0.223 R-free: 0.286

Authors:

J.E.Chrencik,T.E.Benson

Key ref:

J.E.Chrencik et al. (2010). Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol, 400, 413-433. PubMed id: 20478313

Date:

25-Feb-10 Release date: 02-Jun-10

Protein chain

P29597  (TYK2_HUMAN) -  Non-receptor tyrosine-protein kinase TYK2 from Homo sapiens

Seq: 1187 a.a.

Struc: 288 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Mol Biol 400:413-433 (2010)

PubMed id: 20478313

Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6.

J.E.Chrencik, A.Patny, I.K.Leung, B.Korniski, T.L.Emmons, T.Hall, R.A.Weinberg, J.A.Gormley, J.M.Williams, J.E.Day, J.L.Hirsch, J.R.Kiefer, J.W.Leone, H.D.Fischer, C.D.Sommers, H.C.Huang, E.J.Jacobsen, R.E.Tenbrink, A.G.Tomasselli, T.E.Benson.

ABSTRACT

Janus kinases (JAK's) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although crystal structures of active JAK1 and JAK2 kinase domains have recently been reported with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Herein, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization was completed by isothermal titration calorimetry (ITC) for JAK/CP-690550 complex formation, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water beneath the glycine rich loop. Taken together, the data emphasizes the outstanding properties of the kinome selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand binding cavity of the JAK enzymes, as well as the global positioning of the glycine rich loop, may provide the initial clues into obtaining JAK-isozyme selective inhibitors.