1. Department of Biological Sciences, Columbia University, New York, New York 10027, USA
2. These authors contributed equally to this work.

Correspondence to: Liang Tong¹ Correspondence and requests for materials should be addressed to L.T. (Email: ltong@columbia.edu).

Abstract

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis in mammals and is an attractive target for drug discovery against diabetes, obesity and other diseases^{1, 2, 3, 4, 5}. The AMPK homologue in Saccharomyces cerevisiae, known as SNF1, is essential for responses to glucose starvation as well as for other cellular processes, although SNF1 seems to be activated by a ligand other than AMP^{1, 6, 7, 8}. Here we report the crystal structure at 2.6 Å resolution of the heterotrimer core of SNF1. The ligand-binding site in the -subunit (Snf4) has clear structural differences from that of the Schizosaccharomyces pombe enzyme⁹, although our crystallographic data indicate that AMP can also bind to Snf4. The glycogen-binding domain in the -subunit (Sip2) interacts with Snf4 in the heterotrimer but should still be able to bind carbohydrates^{10, 11, 12, 13}. Our structure is supported by a large body of biochemical and genetic data on this complex^{1, 6, 7, 8, 14, 15, 16, 17, 18}. Most significantly, the structure reveals that part of the regulatory sequence in the -subunit (Snf1)^{15, 16, 18, 19} is sequestered by Snf4, demonstrating a direct interaction between the - and -subunits and indicating that our structure may represent the heterotrimer core of SNF1 in its activated state.

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