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. 2013 Dec 19;4:3017. doi: 10.1038/ncomms4017

Figure 3. Structure of full-length AMPK complex with activator.

Figure 3

(a) Bar diagram indicating the three subunits that make up the complex. (b) Cartoon representation of full-length α2β1γ1 in complex with the activator 991, the domains of the three subunits are coloured according to (a). The orientation of the figure is similar to our earlier paper, so that the kinase domain is ‘upside-down’ with respect to the classical kinase orientation. The activator, which binds at the interface of the kinase and CBM, is shown in stick representation with its carbon atoms coloured magenta. Omit density (Fo-Fc) covering the 991 compound is contoured at 2.5 sigma and coloured blue (see also Supplementary Fig. 3). (c) Detailed view of 991 binding in a pocket generated at the interface between the CBM and the kinase domain, and making interactions with a cluster of hydrophobic residues from each domain; Ile-46(Kinase), Phe-90(Kinase), Leu-18(Kinase) and Val-11(Kinase) and Val-81(CBM), Val-113(CBM), Ile-115(CBM) and one of the side-chain carbon atoms (CG) of Thr-106(CBM). These hydrophobic interactions mainly involve ring-1 and ring-2 of the activator (Fig. 1a). The hydrophobic residues from the kinase (yellow) and CBM (green) are shown as sticks with surfaces, while (d) shows the same view and details the polar interactions that contribute to activator binding. Ring-3, and its linkage to ring-2, are involved in a number of polar interactions. Salt-bridges are formed between Asp-88(Kinase) and N2 of ring-2 and Lys-29(Kinase) with the carboxyl group of ring-3. Lys-31(Kinase) interacts with the phosphorylated serine (pSer) at position 108 from the CBM. The CBM contributes an important interaction to drug binding through Arg-83. In addition to making a hydrogen bond with Asn-48(Kinase), it also makes a cation–π stacking interaction with ring-2 of the activator. The cation–π interaction from Arg-83(CBM) with the activator is indicated by hatched lines. Additional potential interactions (where the bond lengths are longer than those expected for a high resolution structure) are indicated by a thin dashed blue line. (e) Overlay of A-769662 (cyan) and 991 (magenta) are shown in stick representation.