3UGC

Structural basis of Jak2 inhibition by the type II inhibtor NVP-BBT594

3UGC の概要

• エントリーDOI: 10.2210/pdb3ugc/pdb
• 分子名称: Tyrosine-protein kinase JAK2, 5-{[6-(acetylamino)pyrimidin-4-yl]oxy}-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-2,3-dihydro-1H-indole-1-carboxamide, MALONATE ION, ... (4 entities in total)
• 機能のキーワード: small molecule inhibitor, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : O60674
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35202.15

構造登録者

Scheufler, C.,Tavares, G.A.,Manley, P.W.,Pissot-Soldermann, C.,Kroemer, M. (登録日: 2011-11-02, 公開日: 2012-05-16, 最終更新日: 2023-09-13)

主引用文献

Andraos, R.,Qian, Z.,Bonenfant, D.,Rubert, J.,Vangrevelinghe, E.,Scheufler, C.,Marque, F.,Regnier, C.H.,De Pover, A.,Ryckelynck, H.,Bhagwat, N.,Koppikar, P.,Goel, A.,Wyder, L.,Tavares, G.,Baffert, F.,Pissot-Soldermann, C.,Manley, P.W.,Gaul, C.,Voshol, H.,Levine, R.L.,Sellers, W.R.,Hofmann, F.,Radimerski, T.
Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
Cancer Discov, 2:512-523, 2012

PubMed Abstract: Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.

PubMed: 22684457
DOI: 10.1158/2159-8290.CD-11-0324

実験手法

X-RAY DIFFRACTION (1.34 Å)