(A) Classification of residues according to their pharmacological
importance (whether a mutation affected signaling or not) and structural
relevance (whether a residue forms an active-state specific contact or not) into
four main classes: bystanders (white), passengers (wheat), modulators (slate)
and drivers (green), the latter is subdivided into connected drivers (driver
residues connected to other driver residues) and unconnected driver residues
(Methods). (B) Position of residues classified by
their participation in active state-specific contacts and importance for
pharmacology on a 2D top view projection of the active, G protein-bound
structure of the β2AR (PDB 3SN6). Frequency of residues along the x- and
y-axis of the receptor (plane parallel to the membrane) is shown on the
distributions outside. Arrows denote the direction of the peaks of the
distribution for the residue classes. Driver residues tend to be in the centre,
whereas bystander residues tend to be at the periphery. (C)
Integration of pharmacologically important residues and the residues
contributing to newly established contacts in the active-state structure yields
the allosteric network for efficacy and potency (see Main text).
(D) Residues forming the allosteric networks for efficacy and
potency are represented as a cartoon, colored by the effect of the mutation. The
graph (left panel) depicts the frequency of potency versus efficacy effects for
residues in the network, projected on the axis running along the extra- to
intra-cellular side. Small circles and their size (scaled to the relative
strength of effect) within each residue indicate the magnitude and effect on
potency and efficacy. Edge thickness in the network corresponds to the number of
contacts, ranging from 1-5.