Structural Insights into the Process of GPCR-G Protein Complex Formation

The crystal structure of the beta 2-adrenergic receptor (beta 2AR) bound to the G protein adenylyl cyclase stimulatory G protein (Gs) captured the complex in a nucleotide-free state (beta 2AR-Gs(empty)). Unfortunately, the beta 2AR-Gs(empty) complex does not provide a clear explanation for G protein coupling specificity. Evidence from several sources suggests the existence of a transient complex between the beta 2AR and GDP-bound Gs protein (beta 2AR-Gs(GDP) ) that may represent an intermediate on the way to the formation of beta 2AR-Gs(empty) and may contribute to coupling specificity. Here we present a structure of the beta 2AR in complex with the carboxyl terminal 14 amino acids from G alpha s along with the structure of the GDP-bound Gs heterotrimer. These structures provide evidence for an alternate interaction between the beta 2AR and Gs that may represent an intermediate that contrib- utes to Gs coupling specificity.