PDBsum entry 4qps

Transferase/transferase inhibitor

PDB id: 4qps

Contents

Protein chains

270 a.a.

276 a.a.

Ligands

37Q ×2

Waters ×199

PDB id:

4qps

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of jak3 complexed to n-[3-(6-phenylamino-pyrazin-2- yl)-3h-benzoimidazol-5-yl]-acrylamide

Structure:

Tyrosine-protein kinase jak3. Chain: a, c. Fragment: jak3, unp residues 811-1103. Synonym: janus kinase 3, jak-3, leukocyte janus kinase, l-jak. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.80Å R-factor: 0.210 R-free: 0.251

Authors:

M.A.Argiriadi,E.R.Goedken

Key ref:

E.R.Goedken et al. (2015). Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. J Biol Chem, 290, 4573-4589. PubMed id: 25552479 DOI: 10.1074/jbc.M114.595181

Date:

24-Jun-14 Release date: 14-Jan-15

Protein chain

P52333  (JAK3_HUMAN) -  Tyrosine-protein kinase JAK3 from Homo sapiens

Seq: 1124 a.a.

Struc: 270 a.a.*

Protein chain

P52333  (JAK3_HUMAN) -  Tyrosine-protein kinase JAK3 from Homo sapiens

Seq: 1124 a.a.

Struc: 276 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, C: 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

DOI no: 10.1074/jbc.M114.595181

J Biol Chem 290:4573-4589 (2015)

PubMed id: 25552479

Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.

E.R.Goedken, M.A.Argiriadi, D.L.Banach, B.A.Fiamengo, S.E.Foley, K.E.Frank, J.S.George, C.M.Harris, A.D.Hobson, D.C.Ihle, D.Marcotte, P.J.Merta, M.E.Michalak, S.E.Murdock, M.J.Tomlinson, J.W.Voss.

ABSTRACT

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.