4M14

Crystal structure of ITK in complex with compound 9 [4-(carbamoylamino)-1-[7-(propan-2-yloxy)naphthalen-1-yl]-1H-pyrazole-3-carboxamide]

4M14 の概要

• エントリーDOI: 10.2210/pdb4m14/pdb
• 関連するPDBエントリー: 4M0Y 4M0Z 4M12 4M13 4M15
• 分子名称: Tyrosine-protein kinase ITK/TSK, 4-(carbamoylamino)-1-[7-(propan-2-yloxy)naphthalen-1-yl]-1H-pyrazole-3-carboxamide (3 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q08881
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31355.75

構造登録者

Han, S.,Caspers, N.L. (登録日: 2013-08-02, 公開日: 2014-04-02, 最終更新日: 2024-02-28)

主引用文献

Han, S.,Czerwinski, R.M.,Caspers, N.L.,Limburg, D.C.,Ding, W.,Wang, H.,Ohren, J.F.,Rajamohan, F.,McLellan, T.J.,Unwalla, R.,Choi, C.,Parikh, M.D.,Seth, N.,Edmonds, J.,Phillips, C.,Shakya, S.,Li, X.,Spaulding, V.,Hughes, S.,Cook, A.,Robinson, C.,Mathias, J.P.,Navratilova, I.,Medley, Q.G.,Anderson, D.R.,Kurumbail, R.G.,Aulabaugh, A.
Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors.
Biochem.J., 460:211-222, 2014

PubMed Abstract: ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.

PubMed: 24593284
DOI: 10.1042/BJ20131139

実験手法

X-RAY DIFFRACTION (1.55 Å)