Department of Discovery Chemistry, Genentech, Inc, South San Francisco, California 94080, USA.
Proteins. 2011 Feb;79(2):393-401. doi: 10.1002/prot.22889.
Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over-stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H-bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC-β4 loop, and it is the only amino acid commonly seen here with H-bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases.
JAK 家族蛋白激酶成员介导细胞因子受体到转录因子激活的信号转导。这些途径的过度刺激是免疫紊乱的原因，如类风湿关节炎、银屑病、狼疮和克罗恩病。对 JAK 激酶选择性抑制剂的研究导致我们对 TYK2 的 Tyr962 通过氢键相互作用与抑制性小分子结合而产生的一种先前未知的激酶构象进行了表征。少数蛋白激酶结构域在 αC-β4 环中的这个位置具有酪氨酸残基，而且这是唯一在这里具有氢键潜力的常见氨基酸。这些发现将有助于设计能够区分 JAK 家族和更广泛的蛋白激酶的抑制剂。
