Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

Christopher G. Langendorf; Kevin R.W. Ngoei; John W. Scott; Naomi X.Y. Ling; Sam M.A. Issa; Michael A. Gorman; Michael W. Parker; Kei Sakamoto; Jonathan S. Oakhill; Bruce E. Kemp

doi:10.1038/ncomms10912

Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

Christopher G. Langendorf, Kevin R.W. Ngoei, John W. Scott, Naomi X.Y. Ling, Sam M.A. Issa, Michael A. Gorman, Michael W. Parker, Kei Sakamoto, Jonathan S. Oakhill, Bruce E. Kemp

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

63 Citations (Scopus)

Abstract

The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.

Original language	English
Article number	10912
Number of pages	8
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10912
Publication status	Published - 8 Mar 2016
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms10912Licence: CC BY

Cite this

@article{3b35154d451f44d59af508489d525c9e,

title = "Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding",

abstract = "The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.",

author = "Langendorf, {Christopher G.} and Ngoei, {Kevin R.W.} and Scott, {John W.} and Ling, {Naomi X.Y.} and Issa, {Sam M.A.} and Gorman, {Michael A.} and Parker, {Michael W.} and Kei Sakamoto and Oakhill, {Jonathan S.} and Kemp, {Bruce E.}",

note = "Funding Information: This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia and we thank the beamline staff for their assistance. This work was supported by grants and fellowships from the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC). Supported in part by the Victorian Government{\textquoteright}s Operational Infrastructure",

year = "2016",

month = mar,

day = "8",

doi = "10.1038/ncomms10912",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

AU - Langendorf, Christopher G.

AU - Ngoei, Kevin R.W.

AU - Scott, John W.

AU - Ling, Naomi X.Y.

AU - Issa, Sam M.A.

AU - Gorman, Michael A.

AU - Parker, Michael W.

AU - Sakamoto, Kei

AU - Oakhill, Jonathan S.

AU - Kemp, Bruce E.

N1 - Funding Information: This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia and we thank the beamline staff for their assistance. This work was supported by grants and fellowships from the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC). Supported in part by the Victorian Government’s Operational Infrastructure

PY - 2016/3/8

Y1 - 2016/3/8

N2 - The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.

AB - The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.

UR - http://www.scopus.com/inward/record.url?scp=84960416125&partnerID=8YFLogxK

U2 - 10.1038/ncomms10912

DO - 10.1038/ncomms10912

M3 - Article

C2 - 26952388

AN - SCOPUS:84960416125

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10912

ER -

Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

Abstract

UN SDGs

Access to Document

Other files and links

Cite this