6B2E

Structure of full length human AMPK (a2b2g1) in complex with a small molecule activator SC4.

6B2E の概要

• エントリーDOI: 10.2210/pdb6b2e/pdb
• 関連するPDBエントリー: 6BIU
• 関連するBIRD辞書のPRD_ID: PRD_900012
• 分子名称: 5'-AMP-activated protein kinase catalytic subunit alpha-2, 5'-AMP-activated protein kinase subunit beta-2, 5'-AMP-activated protein kinase subunit gamma-1, ... (7 entities in total)
• 機能のキーワード: phosphorylated, active, heterotrimer, kinase., transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 135352.02

構造登録者

Ngoei, K.R.W.,Langendorf, C.G.,Ling, N.X.Y.,Hoque, A.,Johnson, S.,Camerino, M.C.,Walker, S.R.,Bozikis, Y.E.,Dite, T.A.,Ovens, A.J.,Smiles, W.J.,Jacobs, R.,Huang, H.,Parker, M.W.,Scott, J.W.,Rider, M.H.,Kemp, B.E.,Foitzik, R.C.,Baell, J.B.,Oakhill, J.S. (登録日: 2017-09-19, 公開日: 2018-04-25, 最終更新日: 2023-10-04)

主引用文献

Ngoei, K.R.W.,Langendorf, C.G.,Ling, N.X.Y.,Hoque, A.,Varghese, S.,Camerino, M.A.,Walker, S.R.,Bozikis, Y.E.,Dite, T.A.,Ovens, A.J.,Smiles, W.J.,Jacobs, R.,Huang, H.,Parker, M.W.,Scott, J.W.,Rider, M.H.,Foitzik, R.C.,Kemp, B.E.,Baell, J.B.,Oakhill, J.S.
Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha 2 beta 2 gamma 1 by the Glucose Importagog SC4.
Cell Chem Biol, 25:728-737.e9, 2018

PubMed Abstract: The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.

PubMed: 29657085
DOI: 10.1016/j.chembiol.2018.03.008

実験手法

X-RAY DIFFRACTION (3.8 Å)