6BX6

AMP-Activated protein kinase (AMPK) inhibition by SBI-0206965: alpha 2 kinase domain bound to SBI-0206965

6BX6 の概要

• エントリーDOI: 10.2210/pdb6bx6/pdb
• 分子名称: 5'-AMP-activated protein kinase catalytic subunit alpha-2, 2-({5-bromo-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}oxy)-N-methylbenzene-1-carboximidic acid (2 entities in total)
• 機能のキーワード: transferase, serine/threonine-protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32071.08

構造登録者

Dite, T.A.,Langendorf, C.G.,Scott, J.W.,Oakhill, J.S. (登録日: 2017-12-17, 公開日: 2018-05-09, 最終更新日: 2023-10-04)

主引用文献

Dite, T.A.,Langendorf, C.G.,Hoque, A.,Galic, S.,Rebello, R.J.,Ovens, A.J.,Lindqvist, L.M.,Ngoei, K.R.W.,Ling, N.X.Y.,Furic, L.,Kemp, B.E.,Scott, J.W.,Oakhill, J.S.
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965.
J. Biol. Chem., 293:8874-8885, 2018

PubMed Abstract: Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor. SBI-0206965 inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C and inhibits cellular AMPK signaling. Biochemical characterization reveals that SBI-0206965 is a mixed-type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows that the drug occupies a pocket that partially overlaps the ATP active site in a type IIb inhibitor manner. SBI-0206965 has utility as a tool compound for investigating physiological roles for AMPK and provides fresh impetus to small-molecule AMPK inhibitor therapeutic development.

PubMed: 29695504
DOI: 10.1074/jbc.RA118.003547

実験手法

X-RAY DIFFRACTION (2.9 Å)