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-Structure paper
タイトル | Structure of an AMPK complex in an inactive, ATP-bound state. |
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ジャーナル・号・ページ | Science, Vol. 373, Issue 6553, Page 413-419, Year 2021 |
掲載日 | 2021年7月23日 |
著者 | 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 / |
PubMed 要旨 | 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 ...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 ATP-bound 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. |
リンク | Science / PubMed:34437114 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.47 - 5.5 Å |
構造データ | EMDB-22336, PDB-7jhg: EMDB-22337, PDB-7jhh: EMDB-23708, PDB-7m74: PDB-7jij: |
化合物 | ChemComp-TAK: ChemComp-ATP: ChemComp-ADP: ChemComp-AMP: |
由来 |
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キーワード | TRANSFERASE/IMMUNE SYSTEM / AMPK / ATP / fully inactive / KD-displaced / TRANSFERASE-IMMUNE SYSTEM complex / SIGNALING PROTEIN / activation / ATP-binding |