6B1U

Structure of full-length human AMPK (a2b1g1) in complex with a small molecule activator SC4

Summary for 6B1U

• Entry DOI: 10.2210/pdb6b1u/pdb
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-2, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (8 entities in total)
• Functional Keywords: phosphorylated, active, heterotrimer, kinase., transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 268631.34

Authors

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. (deposition date: 2017-09-19, release date: 2018-04-25, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.77 Å)