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Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling.

ABSTRACT: 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.

SUBMITTER: Seyedabadi M

PROVIDER: S-EPMC9189013 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling.

Seyedabadi Mohammad M Gharghabi Mehdi M Gurevich Eugenia V EV Gurevich Vsevolod V VV

Trends in biochemical sciences 20220405 7

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 ...[more]

PMID: 35396120

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