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. Author manuscript; available in PMC: 2016 Feb 27.
Published in final edited form as: Nature. 2015 Aug 10;524(7566):497–501. doi: 10.1038/nature14679

Extended Data Figure 5. TMD mutations that introduce basal activity and a positive allosteric modulator increase the affinity and efficacy of a partial agonist.

Extended Data Figure 5

a, Crystal structures of the mGluR1 TMD bound to a NAM (PDB ID: 4OR2) showing the location of conserved residues in TM4 and TM6 previously shown to be sensitive to mutations that induce basal activity. b, Ensemble FRET titrations showing that mutations Q679V and C770A increase the affinity and efficacy of DCG-IV compared to mGluR2wt. c–d, smFRET histograms for TMD mutants show population of the same 3 FRET states as wt, but with greater occupation of the low FRET state at either sub-saturating (c) or saturating (d) concentrations of DCG-IV. e, Binding of PAM LY487379 to the TMD of mGluR2 (top) increases the apparent affinity and efficacy of DCG-IV in ensemble FRET measurements in HEK 293T cells. All values were normalized to the response to 1 mM glutamate. b, smFRET histograms showing a LY487379 -induced shift in the response to 1 μM DCG-IV. Error bars are s.e.m.