5LWN

Crystal structure of JAK3 in complex with Compound 5 (FM409)

5LWN の概要

• エントリーDOI: 10.2210/pdb5lwn/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 1-phenylurea, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: transferase, jak3, covalent inhibitor, reversible covalent inhibitor, induced pocket, arginine pocket, structural genomics, structural genomics consortium, sgc
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : P52333
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34812.88

構造登録者

Chaikuad, A.,Forster, M.,Mukhopadhyay, S.,Kupinska, K.,Ellis, K.,Mahajan, P.,Burgess-Brown, N.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Laufer, S.A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2016-09-18, 公開日: 2016-10-26, 最終更新日: 2024-11-13)

主引用文献

Forster, M.,Chaikuad, A.,Bauer, S.M.,Holstein, J.,Robers, M.B.,Corona, C.R.,Gehringer, M.,Pfaffenrot, E.,Ghoreschi, K.,Knapp, S.,Laufer, S.A.
Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket.
Cell Chem Biol, 23:1335-1340, 2016

PubMed Abstract: Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.

PubMed: 27840070
DOI: 10.1016/j.chembiol.2016.10.008

実験手法

X-RAY DIFFRACTION (1.6 Å)