1. Volume 25, Issue 7, Pages 1153-1162.e4 (July 2017)
Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor 
Laura Pérez-Benito, Maarten L.J. Doornbos, Arnau Cordomí, Luc Peeters, Hilde Lavreysen, Leonardo Pardo, Gary Tresadern 
Structure 
Volume 25, Issue 7, Pages e4 (July 2017)
DOI: /j.str
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2. Structure 2017 25, 1153-1162.e4DOI: (10.1016/j.str.2017.05.021)
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3. Figure 1 Selected mGlu2 Receptor PAMs 1–3 and NAMs 4–6
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4. Figure 2 Key Interactions for PAMs and NAMs
Pharmacophore models of PAMs (A) and NAMs (B) of the mGlu2 receptor. The structural features of the pharmacophore models are shown on the top panels, whereas the predicted amino acids in the mGlu2 receptor, determined by a combination of docking/MD simulations (Figure 3) and mutagenesis experiments (Tables 2 and 3) are shown on the bottom panels. See also Figure S3 for application to mGlu1 receptor.
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5. Figure 3 The Binding Mode of mGlu2 Allosteric Modulators
Detailed view of the binding mode of PAMs 1 (A) green, 2 (B), blue, and 3 (C) yellow and NAMs 4 (D) magenta, 5 (E) orange, and 6 (F) red to the mGlu2 receptor. Amino acids involved in the binding of ligands, as determined by site-directed mutagenesis experiments reported in Tables 2 and 3 are shown in white, whereas S a.35c that was reported for the binding of NAMs to mGlu5 receptor (Gregory et al., 2014) is shown in green. See also Figure S9.
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6. Figure 4 Receptor Side-Chain Movements in Response to NAMs and PAMs
Distribution of the positions of representative atoms (CZ of F a.40c, ND2 of N a.47c, and NE1 of W a.50c) (A and B) and (OH of Y a.44c, CD2 of L a.50c, CG2 of I a.51c, and OG1 of T a.46c) (E and F) of the amino acids of mGlu2 receptor at the homologous positions of the “trigger switch” and “transmission switch” of class A, respectively, during MD simulations of the active-like model of mGlu2 receptor in complex with Gi and PAMs 1–3 (B and F) and of the “inactive” model in complex with NAMs 4–6 (A and E). Evenly spaced snapshots extracted from the 1 μs of unbiased MD simulations are depicted. PAMs 1–3 are shown in green, blue and yellow and NAMs 4–6 are shown in magenta, orange, and red, respectively. Time-evolution of the χ1 rotamer of W a.50c and T a.46c for NAMs 4–6 (C and G) and PAMs 1–3 (D and H) during the MD simulations (line color matches with the bound ligand). See also Figures S7 and S8 for application to mGlu1 and mGlu5 receptors.
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7. Figure 5
Comparison of the Mechanism of Positive and Negative Allosteric Modulation at the mGlu2 Receptor
Relative position of the “trigger switch” amino acids involved in the initial agonist-induced structural changes on the receptor responsible for the rearrangement of the “transmission switch” amino acids that finally lead to receptor activation during MD simulations of PAM 1 (in green) and NAM 6 (in red) (see legend of Figure 4 for details of the MD simulations and the atoms depicted).
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8. Figure 6
Mutation of Transmission Switch Amino Acids and Effect on Functional Glutamate-Induced [35S]GTPγS Binding
Curves show the glutamate concentration response for mutants Y a.44cA/F and T a.46cA/S. Error bars show SDs.
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