4qps
Crystal structure of Jak3 complexed to N-[3-(6-Phenylamino-pyrazin-2-yl)-3H-benzoimidazol-5-yl]-acrylamide
Structural highlights
DiseaseJAK3_HUMAN Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] [2] [3] [:][4] [5] [6] [7] [8] FunctionJAK3_HUMAN Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.[9] [10] [11] Publication Abstract from PubMedThe 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 & psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, 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 (Cys909). 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. Tricyclic Covalent Inhibitors Selectively Target Jak3 Through an Active-site Thiol.,Goedken ER, Argiriadi MA, Banach DL, Fiamengo BA, Foley SE, Frank KE, George JS, Harris CM, Hobson AD, Ihle DC, Marcotte D, Merta PJ, Michalak ME, Murdock SE, Tomlinson MJ, Voss JW J Biol Chem. 2014 Dec 31. pii: jbc.M114.595181. PMID:25552479[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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