6ES0

Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35

6ES0 の概要

• エントリーDOI: 10.2210/pdb6es0/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 2, 2-[2-fluoranyl-4-[[2-fluoranyl-4-[2-(methylcarbamoyl)pyridin-4-yl]oxy-phenyl]carbamoylamino]phenyl]sulfanylethanoic acid (3 entities in total)
• 機能のキーワード: kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73748.63

構造登録者

Pinkas, D.M.,Bufton, J.C.,Suebsuwong, C.,Ray, S.S.,Dai, B.,Newman, J.A.,Burgess-Brown, N.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Degterev, A.,Cuny, G.D.,Bullock, A.N. (登録日: 2017-10-19, 公開日: 2018-02-21, 最終更新日: 2024-01-17)

主引用文献

Suebsuwong, C.,Pinkas, D.M.,Ray, S.S.,Bufton, J.C.,Dai, B.,Bullock, A.N.,Degterev, A.,Cuny, G.D.
Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.
Bioorg. Med. Chem. Lett., 28:577-583, 2018

PubMed Abstract: Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.

PubMed: 29409752
DOI: 10.1016/j.bmcl.2018.01.044

実験手法

X-RAY DIFFRACTION (2.38 Å)