Structural dynamics bridge the gap between the genetic and functional levels of GPCRs

G protein–coupled receptors (GPCRs) are implicated in nearly all physiological processes in the human body and represent an important drug targeting class. The genes encoding the different GPCR (sub)types determine their specific functionality, which can be altered by natural genetic variants and isoforms. Deciphering the molecular link between sequence diversity and its functional consequences is a current challenge and critical for the comprehension of the physiological response of GPCRs. It requires a global understanding of how protein sequence translates into protein structure, how this impacts the structural motions of the protein, and, finally, how all these factors determine the receptor functionality. Here, we discuss available resources and state-of-the-art computational approaches to address this question.