Molecular basis for dramatic changes in cannabinoid CB1 G protein-coupled receptor activation upon single and double point mutations.

ABSTRACT: There is considerable interest in determining the activation mechanism of G protein-coupled receptors (GPCRs), one of the most important types of proteins for intercellular signaling. Recently, it was demonstrated for the cannabinoid CB1 GPCR, that a single mutation T210A could make CB1 completely inactive whereas T210I makes it essentially constitutively active. To obtain an understanding of this dramatic dependence of activity on mutation, we used first-principles-based methods to predict the ensemble of low-energy seven-helix conformations for the wild-type (WT) and mutants (T210A and T210I). We find that the transmembrane (TM) helix packings depend markedly on these mutations, leading for T210A to both TM3+TM6 and TM2+TM6 salt-bridge couplings in the cytoplasmic face that explains the

SUBMITTER: Scott CE 

PROVIDER: S-EPMC3575865 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature