5t5t | pdb_00005t5t
AMPK bound to allosteric activator
Structural highlights
FunctionAAKB1_RAT Non-catalytic 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. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3). Publication Abstract from PubMedDiabetic nephropathy remains an area of high unmet medical need, with current therapies slowing, but not preventing the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both human subjects and animal models of kidney disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the beta1 subunit. After confirming that human and rodent kidney predominately express AMPK beta1, we explore the effects of pharmacologic activation of AMPK in the ZSF-1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevate the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduce the progression of proteinuria to a greater degree than the ACE-inhibitor ramipril. Further analysis of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease. Selective Activation of AMPK b1-containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.,Salatto CT, Miller RA, Cameron KO, Cokorinos E, Reyes A, Ward J, Calabrese M, Kurumbail R, Rajamohan F, Kalgutkar AS, Tess DA, Shavnya A, Genung NE, Edmonds DJ, Jatkar A, Maciejewski BS, Amaro M, Gandhok H, Monetti M, Cialdea K, Bollinger E, Kreeger JM, Coskran TM, Opsahl AC, Boucher GG, Birnbaum MJ, DaSilva-Jardine P, Rolph T J Pharmacol Exp Ther. 2017 Mar 13. pii: jpet.116.237925. doi:, 10.1124/jpet.116.237925. PMID:28289077[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
