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AMP-activated protein kinase undergoes nucleotide-dependent conformational changes

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Abstract

The energy sensor AMP-activated protein kinase (AMPK) is a heterotrimeric complex that is allosterically activated by AMP binding to the γ subunit. Cocrystal structures of the mammalian AMPK core reveal occlusion of nucleotide-binding site 3 of the γ subunit in the presence of ATP. However, site 3 is occupied in the presence of AMP. Mutagenesis studies indicate that sites 3 and 4 are important for AMPK allosteric activation.

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Figure 1: AMPK core structures in complex with ATP or AMP.
Figure 2: Conformational changes between the AMP-bound and ATP-bound AMPK γ subunits.
Figure 3: Identification of regulatory sites 3 and 4 for allosteric stimulation.

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Acknowledgements

We thank S.C. Lin for critical discussions and reading of the manuscript. Crystallographic data were collected at Shanghai Synchrotron Radiation Facility beamline 17U. This work is supported in part by grant 2011CB910800 (National Key Basic Research Program of China) to J.-W.W. and Z.-X.W. and grants 31130062, 31070643 (Natural Science Foundation of China) and 09THZ02235 (Tsinghua University) to J.-W.W.

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Author notes

  1. Lei Chen

    Present address: Present address: Vollum Institute, Oregon Health & Science University, Portland, Oregon, USA.,

Authors and Affiliations

  1. MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Lei Chen, Jue Wang, Yuan-Yuan Zhang, Zhi-Xin Wang & Jia-Wei Wu

  2. Molecular Design and Biostructure, Roche Pharma Research and Early Development, Shanghai, China

    S Frank Yan

  3. Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands

    Dietbert Neumann

  4. Institut National de la Santé et de la Recherche Médicale, Grenoble, France

    Uwe Schlattner

  5. Laboratory of Fundamental and Applied Bioenergetics, University Joseph Fourier, Grenoble, France

    Uwe Schlattner

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  1. Lei Chen
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  2. Jue Wang
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  7. Zhi-Xin Wang
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  8. Jia-Wei Wu
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Contributions

L.C., J.W. and Y.-Y.Z. performed experiments; S.F.Y., D.N., U.S., Z.-X.W. and J.-W.W. contributed to discussions and manuscript writing.

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Correspondence to Jia-Wei Wu.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2, Supplementary Note (PDF 1641 kb)

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Chen, L., Wang, J., Zhang, YY. et al. AMP-activated protein kinase undergoes nucleotide-dependent conformational changes. Nat Struct Mol Biol 19, 716–718 (2012). https://doi.org/10.1038/nsmb.2319

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  • DOI: https://doi.org/10.1038/nsmb.2319

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