6E4W

Structure of AMPK bound to activator

6E4W の概要

• エントリーDOI: 10.2210/pdb6e4w/pdb
• 分子名称: 5'-AMP-activated protein kinase catalytic subunit alpha-1, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (9 entities in total)
• 機能のキーワード: kinase, ampk, activator, allostery, transferase-activator complex, transferase
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 120634.54

構造登録者

Calabrese, M.F.,Kurumbail, R.G. (登録日: 2018-07-18, 公開日: 2018-08-08, 最終更新日: 2024-10-23)

主引用文献

Ryder, T.F.,Calabrese, M.F.,Walker, G.S.,Cameron, K.O.,Reyes, A.R.,Borzilleri, K.A.,Delmore, J.,Miller, R.,Kurumbail, R.G.,Ward, J.,Kung, D.W.,Brown, J.A.,Edmonds, D.J.,Eng, H.,Wolford, A.C.,Kalgutkar, A.S.
Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK).
J. Med. Chem., 61:7273-7288, 2018

PubMed Abstract: Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1-3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1-3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1-3 and M1-M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

PubMed: 30036059
DOI: 10.1021/acs.jmedchem.8b00807

実験手法

X-RAY DIFFRACTION (3.35 Å)