Universal Activation Index for Class A GPCRs

An index of the activation of Class
A G-protein-coupled receptors
(GPCRs) has been trained using interhelix distances from a series
of microsecond molecular-dynamics simulations and tested for 268 published
X-ray structures. In a three-class model that includes intermediate
structures, 63% of the active structures are classified in agreement
with the experimental assignment, 81% of the intermediate structures,
and 89% of the inactives. An alternative two-state model classifies
94% of the actives and 99% of the inactives correctly. The intermediate
structures are distributed 2:1 between actives and inactives. X-ray
structures with protein nanobodies give good agreement between the
assigned activation state and the predictions of the model, whereby
many active nanobody structures are predicted to be weakly active.
The five interhelix Cα–Cα distances that occur in the model relate clearly to the established
activation mechanism. The model is available as a Python script or
via an interactive web page. It can thus be used to classify both
experimental and computational GPCR structures.