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Three classes of G-protein-coupled receptor (GPCR) partners - G proteins, GPCR kinases, and arrestins - preferentially bind active GPCRs. Our analysis suggests that the structures of GPCRs bound to these interaction partners available today do not reveal a clear conformational basis for signaling bias, which would have enabled the rational design of biased GRCR ligands. In view of this, three possibilities are conceivable: (i) there are no generalizable GPCR conformations conducive to binding a particular type of partner; (ii) subtle differences in the orientation of individual residues and/or their interactions not easily detectable in the receptor-transducer structures determine partner preference; or (iii) the dynamics of GPCR binding to different types of partners rather than the structures of the final complexes might underlie transducer bias. |
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