6b1u
From Proteopedia
Structure of full-length human AMPK (a2b1g1) in complex with a small molecule activator SC4
Structural highlights
FunctionAAKG1_HUMAN AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.[1] Publication Abstract from PubMedThe AMP-activated protein kinase (AMPK) alphabetagamma heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle alpha2beta2 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 alpha2 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 alpha2beta2gamma1 and alpha2beta1gamma1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and beta2-Asp111, which provide a design paradigm for beta2-AMPK therapeutics. The alpha2beta2gamma1/SC4 structure reveals an interaction between a beta2 N-terminal alpha helix and the alpha2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, beta2-AMPK therapeutics. Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha2beta2gamma1 by the Glucose Importagog SC4.,Ngoei KRW, Langendorf CG, Ling NXY, Hoque A, Varghese S, Camerino MA, Walker SR, Bozikis YE, Dite TA, Ovens AJ, Smiles WJ, Jacobs R, Huang H, Parker MW, Scott JW, Rider MH, Foitzik RC, Kemp BE, Baell JB, Oakhill JS Cell Chem Biol. 2018 Apr 12. pii: S2451-9456(18)30110-7. doi:, 10.1016/j.chembiol.2018.03.008. PMID:29657085[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Baell JB | Bozikis YE | Camerino MC | Dite TA | Foitzik RC | Hoque A | Huang H | Jacobs R | Johnson S | Kemp BE | Langendorf CG | Ling NXY | Ngoei KRW | Oakhill JS | Ovens AJ | Parker MW | Rider MH | Scott JW | Smiles WJ | Walker SR
