Structure and Regulation of AMPK

  • Ravi G. KurumbailEmail author
  • Matthew F. Calabrese
Part of the Experientia Supplementum book series (EXS, volume 107)


AMP-activated protein kinase is a family of heterotrimeric serine/threonine protein kinases that come in twelve different flavors. They serve an essential function in all eukaryotes of conserving cellular energy levels. AMPK complexes are regulated by changes in cellular AMP:ATP or ADP:ATP ratios and by a number of neutraceuticals and some of the widely-used diabetes medications such as metformin and thiazolinonediones. Moreover, biochemical activities of AMPK are tightly regulated by phosphorylation or dephosphorylation by upstream kinases and phosphatases respectively. Efforts are underway in many pharmaceutical companies to discover direct AMPK activators for the treatment of cardiovascular and metabolic diseases such as diabetes, non-alcoholic steatohepatitis (NASH) and diabetic nephropathy. Many advances have been made in the AMPK structural biology arena over the last few years that are beginning to provide detailed molecular insights into the overall topology of these fascinating enzymes and how binding of small molecules elicit subtle conformational changes leading to their activation and protection from dephosphorylation. In the brief review below on AMPK structure and function, we have focused on the recent crystallographic results especially on specific molecular interactions of direct synthetic AMPK activators which lead to biased activation of a sub-family of AMPK isoforms.


X-ray Crystallography Enzyme activators Allostery AMPK 


  1. Ahn J, Lee H, Kim S, Park J, Ha T (2008) The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 373:545–549CrossRefPubMedGoogle Scholar
  2. Amodeo GA, Rudolph MJ, Tong L (2007) Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449:492–495CrossRefPubMedGoogle Scholar
  3. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342CrossRefPubMedPubMedCentralGoogle Scholar
  4. Calabrese MF, Rajamohan F, Harris MS, Caspers NL, Magyar R, Withka JM, Wang H, Borzilleri KA, Sahasrabudhe PV, Hoth LR et al (2014) Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure 22:1161–1172CrossRefPubMedGoogle Scholar
  5. Carling D, Viollet B (2015) Beyond energy homeostasis: the expanding role of AMP-activated protein kinase in regulating metabolism. Cell Metab 21:799–804CrossRefPubMedGoogle Scholar
  6. Carling D, Zammit VA, Hardie DG (1987) A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 223:217–222CrossRefPubMedGoogle Scholar
  7. Carling D, Clarke PR, Zammit VA, Hardie DG (1989) Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur J Biochem 182:129–136CrossRefGoogle Scholar
  8. Chen L, Jiao ZH, Zheng LS, Zhang YY, Xie ST, Wang ZX, Wu JW (2009) Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature 459:1146–1149CrossRefPubMedGoogle Scholar
  9. Chen L, Wang J, Zhang YY, Yan SF, Neumann D, Schlattner U, Wang ZX, Wu JW (2012) AMP-activated protein kinase undergoes nucleotide-dependent conformational changes. Nat Struct Mol Biol 19:716–718CrossRefPubMedGoogle Scholar
  10. Chen L, Xin FJ, Wang J, Hu J, Zhang YY, Wan S, Cao LS, Lu C, Li P, Yan SF et al (2013) Conserved regulatory elements in AMPK. Nature 498:E8–E10CrossRefPubMedGoogle Scholar
  11. Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D (2000) Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding. Biochem J 346:659–669CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R et al (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416CrossRefPubMedGoogle Scholar
  13. Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-Aminoimidazole-4-Carboxamide Ribonucleoside. Eur J Biochem 229:558–565CrossRefPubMedGoogle Scholar
  14. Crute BE, Seefeld K, Gamble J, Kemp BE, Witters LA (1998) Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J Biol Chem 273:35347–35354CrossRefPubMedGoogle Scholar
  15. Dale S, Wilson WA, Edelman AM, Hardie DG (1995) Similar substrate recognition motifs for mammalian AMP-activated protein kinase, higher plant HMG-CoA reductase kinase-A, yeast SNF1, and mammalian calmodulin-dependent protein kinase I. FEBS Lett 361:191–195CrossRefPubMedGoogle Scholar
  16. Davies SP, Helps NR, Cohen PT, Hardie DG (1995) 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 377:421–425CrossRefPubMedGoogle Scholar
  17. Day P, Sharff A, Parra L, Cleasby A, Williams M, Horer S, Nar H, Redemann N, Tickle I, Yon J (2007) Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallogr D Biol Crystallogr 63:587–596CrossRefPubMedGoogle Scholar
  18. Fryer LG, Parbu-Patel A, Carling D (2002) The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232CrossRefPubMedGoogle Scholar
  19. Gómez-Galeno JE, Dang Q, Nguyen TH, Boyer SH, Grote MP, Sun Z, Chen M, Craigo WA, van Poelje PD, MacKenna DA et al (2010) A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med Chem Lett 1:478–482CrossRefPubMedPubMedCentralGoogle Scholar
  20. Goransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K (2007) Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem 282:32549–32560CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gowans GJ, Hawley SA, Ross FA, Hardie DG (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 18:556–566CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226CrossRefPubMedPubMedCentralGoogle Scholar
  23. Handa N, Takagi T, Saijo S, Kishishita S, Takaya D, Toyama M, Terada T, Shirouzu M, Suzuki A, Lee S et al (2011) Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain. Acta Crystallogr D Biol Crystallogr 67:480–487CrossRefPubMedGoogle Scholar
  24. Hardie DG (2016) Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharm Sin B 6:1–19CrossRefGoogle Scholar
  25. Hawley SA, Davison M, Davies SP, Beri RK, Carling D, Hardie DG (1996) Characterization of the AMP-activated protein kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271:27879–27887CrossRefPubMedGoogle Scholar
  26. Hawley SA, Gadalla AE, Olsen GS, Hardie DG (2002) The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51:2420–2425CrossRefPubMedGoogle Scholar
  27. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG (2003) Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hawley SA, Pan DA, Mustark KJ, Ross L, Bain J, Edelman AM, Frenquelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19CrossRefPubMedGoogle Scholar
  29. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11:554–565CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ et al (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336:918–922CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M, Ross FA, Hawley SA, Shpiro N, Viollet B, Barron D et al (2014) Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK. Chem Biol 21:866–879CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA (2005) The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280:29060–29066CrossRefPubMedGoogle Scholar
  33. Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, Ha J, Park OJ (2005) Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 338:694–699CrossRefPubMedGoogle Scholar
  34. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590CrossRefPubMedGoogle Scholar
  35. Jensen TE, Ross FA, Kleinert M, Sylow L, Knudsen JR, Gowans GJ, Hardie DG, Richter EA (2015) PT-1 selectively activates AMPK-gamma1 complexes in mouse skeletal muscle, but activates all three gamma subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochem J 467:461–472CrossRefPubMedGoogle Scholar
  36. Jin X, Townley R, Shapiro L (2007) Structural insight into AMPK regulation: ADP comes into play. Structure 15:1285–1295CrossRefPubMedGoogle Scholar
  37. Kemp BE, Oakhill JS, Scott JW (2007) AMPK structure and regulation from three angles. Structure 15:1161–1163CrossRefPubMedGoogle Scholar
  38. Koay A, Rimmer KA, Mertens HDT, Gooley PR, Stapleton D (2007) Oligosaccharide recognition and binding to the carbohydrate binding module of AMP‐activated protein kinase. FEBS Lett 581:5055–5059CrossRefPubMedGoogle Scholar
  39. Koay A, Woodcroft B, Petrie EJ, Yue H, Emanuelle S, Bieri M, Bailey MF, Hargreaves M, Park J-T, Park K-H et al (2010) AMPK β subunits display isoform specific affinities for carbohydrates. FEBS Lett 584:3499–3503CrossRefPubMedGoogle Scholar
  40. Kudo N, Gillespie JG, Kung L, Witters LA, Schulz R, Clanachan AS, Lopaschuk GD (1996) Characterization of 5′AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1301:67–75CrossRefPubMedGoogle Scholar
  41. Landgraf RR, Goswami D, Rajamohan F, Harris MS, Calabrese MF, Hoth LR, Magyar R, Pascal BD, Chalmers MJ, Busby SA et al (2013) Activation of AMP-activated protein kinase revealed by hydrogen/deuterium exchange mass spectrometry. Structure 21:1942–1953CrossRefPubMedGoogle Scholar
  42. Langendorf CG, Kemp BE (2015) Choreography of AMPK activation. Cell Res 25:5–6CrossRefPubMedGoogle Scholar
  43. Langendorf CG, Ngoei KR, Scott JW, Ling NX, Issa SM, Gorman MA, Parker MW, Sakamoto K, Oakhill JS, Kemp BE (2016) Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nat Commun 7:10912CrossRefPubMedPubMedCentralGoogle Scholar
  44. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT et al (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55:2256–2264CrossRefPubMedGoogle Scholar
  45. Li X, Wang L, Zhou XE, Ke J, de Waal PW, Gu X, Tan MH, Wang D, Wu D, Xu HE et al (2015) Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res 25:50–66CrossRefPubMedGoogle Scholar
  46. Littler DR, Walker JR, Davis T, Wybenga-Groot LE, Finerty PJ Jr, Newman E, Mackenzie F, Dhe-Paganon S (2010) A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:143–151CrossRefPubMedPubMedCentralGoogle Scholar
  47. Mayer FV, Heath R, Underwood E, Sanders MJ, Carmena D, McCartney RR, Leiper FC, Xiao B, Jing C, Walker PA et al (2011) ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase. Cell Metab 14:707–714CrossRefPubMedPubMedCentralGoogle Scholar
  48. McBride A, Hardie DG (2009) AMP-activated protein kinase—a sensor of glycogen as well as AMP and ATP? Acta Physiol (Oxf) 196:99–113CrossRefGoogle Scholar
  49. McBride A, Ghilagaber S, Nikolaev A, Hardie DG (2009) The glycogen-binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor. Cell Metab 9:23–34CrossRefPubMedPubMedCentralGoogle Scholar
  50. Mobbs JI, Koay A, Di Paolo A, Bieri M, Petrie EJ, Gorman MA, Doughty L, Parker MW, Stapleton D, Griffin MD et al (2015a) Determinants of oligosaccharide specificity of the carbohydrate binding modules of AMP-activated protein kinase. Biochem J 468:245–257Google Scholar
  51. Mobbs JI, Koay A, Di Paolo A, Bieri M, Petrie EJ, Gorman MA, Doughty L, Parker MW, Stapleton DI, Griffin MD et al (2015b) Determinants of oligosaccharide specificity of the carbohydrate-binding modules of AMP-activated protein kinase. Biochem J 468:245–257Google Scholar
  52. Mounier R, Theret M, Lantier L, Foretz M, Viollet B (2015) Expanding roles for AMPK in skeletal muscle plasticity. Trends Endocrinol Metab 26:275–286CrossRefPubMedGoogle Scholar
  53. Nayak V, Zhao K, Wyce A, Schwartz MF, Lo WS, Berger SL, Marmorstein R (2006) Structure and dimerization of the kinase domain from yeast Snf1, a member of the Snf1/AMPK protein family. Structure 14:477–485CrossRefPubMedGoogle Scholar
  54. Neumann D, Woods A, Carling D, Wallimann T, Schlattner U (2003) Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expr Purif 30:230–237CrossRefPubMedGoogle Scholar
  55. Neumann D, Wallimann T, Rider MH, Tokarska-Schlattner M, Hardie DG, Schlattner U (2007) Signaling by AMP-activated protein kinase. In: Saks V (ed) Molecular system bioenergetics. Wiley, Weinheim, pp 303–338CrossRefGoogle Scholar
  56. Oakhill JS, Chen Z-P, Scott JW, Steel R, Castelli LA, Ling N, Macaulay SL, Kemp BE (2010) β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci USA 107:19237–19241CrossRefPubMedPubMedCentralGoogle Scholar
  57. Oakhill JS, Steel R, Chen Z-P, Scott JW, Ling N, Tam S, Kemp BE (2011) AMPK is a direct adenylate charge-regulated protein kinase. Science 332:1433–1435CrossRefPubMedGoogle Scholar
  58. Oakhill JS, Scott JW, Kemp BE (2012) AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab 23:125–132CrossRefPubMedGoogle Scholar
  59. Pang T, Zhang ZS, Gu M, Qiu BY, Yu LF, Cao PR, Shao W, Su MB, Li JY, Nan FJ et al (2008) Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J Biol Chem 283:16051–16060CrossRefPubMedPubMedCentralGoogle Scholar
  60. Polekhina G, Gupta A, Michell BJ, van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW et al (2003) AMPK β subunit targets metabolic stress sensing to glycogen. Curr Biol 13:867–871CrossRefPubMedGoogle Scholar
  61. Polekhina G, Gupta A, van Denderen BJ, Feil SC, Kemp BE, Stapleton D, Parker MW (2005) Structural basis for glycogen recognition by AMP-activated protein kinase. Structure 10:1453–1462CrossRefGoogle Scholar
  62. Rajamohan F, Harris MS, Frisbie RK, Hoth LR, Geoghegan KF, Valentine JJ, Reyes AR, Landro JA, Qiu X, Kurumbail RG (2010) Escherichia coli expression, purification and characterization of functional full-length recombinant α2β2γ3 heterotrimeric complex of human AMP-activated protein kinase. Protein Expr Purif 73:189–197CrossRefPubMedGoogle Scholar
  63. Rajamohan F, Reyes AR, Frisbie RK, Hoth LR, Sahasrabudhe P, Magyar R, Landro JA, Withka JM, Caspers NL, Calabrese MF et al (2015) Probing the enzyme kinetics, allosteric modulation and activation of alpha-1 and alpha-2 subunit containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem J 473:581–592Google Scholar
  64. Riek U, Scholz R, Konarev P, Rufer A, Suter M, Nazabal A, Ringler P, Chami M, Muller SA, Neumann D et al (2008) Structural properties of AMP-activated protein kinase: dimerization, molecular shape, and changes upon ligand binding. J Biol Chem 283:18331–18343CrossRefPubMedGoogle Scholar
  65. Ross FA, Jensen TE, Hardie DG (2016a) Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem J 473:189–199Google Scholar
  66. Ross FA, MacKintosh C, Hardie DG (2016b) AMP-activated protein kinase: a cellular energy sensor that comes in twelve flavours. FEBS J. doi: 10.1111/febs.13698 Google Scholar
  67. Rudolph MJ, Amodeo GA, Iram SH, Hong SP, Pirino G, Carlson M, Tong L (2007) Structure of the Bateman2 domain of yeast Snf4: dimeric association and relevance for AMP binding. Structure 15:65–74CrossRefPubMedGoogle Scholar
  68. Rudolph MJ, Amodeo GA, Tong L (2010) An inhibited conformation for the protein kinase domain of the Saccharomyces cerevisiae AMPK homolog Snf1. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:999–1002CrossRefPubMedPubMedCentralGoogle Scholar
  69. Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D (2007) Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 282:32539–32548CrossRefPubMedGoogle Scholar
  70. Scott JW, van Denderen BJ, Jorgensen SB, Honeyman JE, Steinberg GR, Oakhill JS, Iseli TJ, Koay A, Gooley PR, Stapleton D et al (2008) Thienopyridone drugs are selective activators of AMP-activated protein kinase β1-containing complexes. Chem Biol 15:1220–1230CrossRefPubMedGoogle Scholar
  71. Scott JW, Ling N, Issa SMA, Dite TA, O’Brien MT, Chen ZP, Galic S, Langendorf CG, Steinberg GR, Kemp BE et al (2014) Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem Biol 21:1–9CrossRefGoogle Scholar
  72. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci 101:3329–3335CrossRefPubMedPubMedCentralGoogle Scholar
  73. Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078CrossRefPubMedGoogle Scholar
  74. Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281:32207–32216CrossRefPubMedGoogle Scholar
  75. Townley R, Shapiro L (2007) Crystal structures of the adenylate sensor form fission yeast AMP-activated protein kinase. Science 315:1726–1729CrossRefPubMedGoogle Scholar
  76. Walker JR, Wybenga-Groot L, Finerty Jr PJ, Newman E, Mackenzie FM, Weigelt J, Sundstrom M, Arrowsmith C, Edwards A, Bochkarev A, Structural Genomics Consortium et al (2005) Structure of the glycogen-binding domain of the AMP-activated protein kinase beta2 subunit, PDB accession code, 2F15Google Scholar
  77. Warden SM, Richardson C, O’Donnell J Jr, Stapleton D, Kemp BE, Witters LA (2001) Post-translational modifications of the β1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem J 354:275–283CrossRefPubMedPubMedCentralGoogle Scholar
  78. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003a) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13:2004–2008CrossRefPubMedGoogle Scholar
  79. Woods A, Vertommen D, Neumann D, Turk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH (2003b) Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 278:28434–28443CrossRefPubMedGoogle Scholar
  80. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D (2005) Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2:21–33CrossRefPubMedGoogle Scholar
  81. Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT et al (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449:496–500CrossRefPubMedGoogle Scholar
  82. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF et al (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472:230–233CrossRefPubMedPubMedCentralGoogle Scholar
  83. Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S et al (2013) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:2017Google Scholar
  84. Xin FJ, Wang J, Zhao RQ, Wang ZX, Wu JW (2013) Coordinated regulation of AMPK activity by multiple elements in the alpha-subunit. Cell Res 10:1237–1240CrossRefGoogle Scholar
  85. Yu LF, Li YY, Su MB, Zhang M, Zhang W, Zhang LN, Pang T, Zhang RT, Liu B, Li JY et al (2013) Development of novel alkene oxindole derivatives as orally efficacious AMP-activated protein kinase activators. ACS Med Chem Lett 4:475–480CrossRefPubMedPubMedCentralGoogle Scholar
  86. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174CrossRefPubMedPubMedCentralGoogle Scholar
  87. Zhu L, Chen L, Zhou XM, Zhang YY, Zhang YJ, Zhao J, Ji SR, Wu JW, Wu Y (2011) Structural insights into the architecture and allostery of full-length AMP-activated protein kinase. Structure 19:515–522CrossRefPubMedGoogle Scholar
  88. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99:15983–15987CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Pfizer Worldwide Research and Development, Pfizer IncGrotonUSA

Personalised recommendations