Structure of an AMPK complex in an inactive, ATP-bound state

Yan Yan; Somnath Mukherjee; Kaleeckal G. Harikumar; Timothy S. Strutzenberg; X. Edward Zhou; Kelly Suino-Powell; Ting Hai Xu; Ryan D. Sheldon; Jared Lamp; Joseph S. Brunzelle; Katarzyna Radziwon; Abigail Ellis; Scott J. Novick; Irving E. Vega; Russell G. Jones; Laurence J. Miller; H. Eric Xu; Patrick R. Griffin; Anthony A. Kossiakoff; Karsten Melcher

doi:10.1126/science.abe7565

Structure of an AMPK complex in an inactive, ATP-bound state

Yan Yan, Somnath Mukherjee, Kaleeckal G. Harikumar, Timothy S. Strutzenberg, X. Edward Zhou, Kelly Suino-Powell, Ting Hai Xu, Ryan D. Sheldon, Jared Lamp, Joseph S. Brunzelle, Katarzyna Radziwon, Abigail Ellis, Scott J. Novick, Irving E. Vega, Russell G. Jones, Laurence J. Miller, H. Eric Xu, Patrick R. Griffin, Anthony A. Kossiakoff, Karsten Melcher

Research output: Contribution to journal › Article › peer-review

Abstract

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATPbound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180° rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.

Original language	English (US)
Pages (from-to)	413-419
Number of pages	7
Journal	Science
Volume	373
Issue number	6553
DOIs	https://doi.org/10.1126/science.abe7565
State	Published - Jul 23 2021

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Yan, Y., Mukherjee, S., Harikumar, K. G., Strutzenberg, T. S., Zhou, X. E., Suino-Powell, K., Xu, T. H., Sheldon, R. D., Lamp, J., Brunzelle, J. S., Radziwon, K., Ellis, A., Novick, S. J., Vega, I. E., Jones, R. G., Miller, L. J., Xu, H. E., Griffin, P. R., Kossiakoff, A. A., & Melcher, K. (2021). Structure of an AMPK complex in an inactive, ATP-bound state. Science, 373(6553), 413-419. https://doi.org/10.1126/science.abe7565

Yan, Y, Mukherjee, S, Harikumar, KG, Strutzenberg, TS, Zhou, XE, Suino-Powell, K, Xu, TH, Sheldon, RD, Lamp, J, Brunzelle, JS, Radziwon, K, Ellis, A, Novick, SJ, Vega, IE, Jones, RG, Miller, LJ, Xu, HE, Griffin, PR, Kossiakoff, AA & Melcher, K 2021, 'Structure of an AMPK complex in an inactive, ATP-bound state', Science, vol. 373, no. 6553, pp. 413-419. https://doi.org/10.1126/science.abe7565

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title = "Structure of an AMPK complex in an inactive, ATP-bound state",

abstract = "Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATPbound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180° rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.",

author = "Yan Yan and Somnath Mukherjee and Harikumar, {Kaleeckal G.} and Strutzenberg, {Timothy S.} and Zhou, {X. Edward} and Kelly Suino-Powell and Xu, {Ting Hai} and Sheldon, {Ryan D.} and Jared Lamp and Brunzelle, {Joseph S.} and Katarzyna Radziwon and Abigail Ellis and Novick, {Scott J.} and Vega, {Irving E.} and Jones, {Russell G.} and Miller, {Laurence J.} and Xu, {H. Eric} and Griffin, {Patrick R.} and Kossiakoff, {Anthony A.} and Karsten Melcher",

year = "2021",

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doi = "10.1126/science.abe7565",

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AU - Yan, Yan

AU - Mukherjee, Somnath

AU - Harikumar, Kaleeckal G.

AU - Strutzenberg, Timothy S.

AU - Zhou, X. Edward

AU - Suino-Powell, Kelly

AU - Xu, Ting Hai

AU - Sheldon, Ryan D.

AU - Lamp, Jared

AU - Brunzelle, Joseph S.

AU - Radziwon, Katarzyna

AU - Ellis, Abigail

AU - Novick, Scott J.

AU - Vega, Irving E.

AU - Jones, Russell G.

AU - Miller, Laurence J.

AU - Xu, H. Eric

AU - Griffin, Patrick R.

AU - Kossiakoff, Anthony A.

AU - Melcher, Karsten

PY - 2021/7/23

Y1 - 2021/7/23

N2 - Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATPbound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180° rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.

AB - Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATPbound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180° rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.

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Structure of an AMPK complex in an inactive, ATP-bound state

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