Faculty Collaboration Database

Structural insights into differences in G protein activation by family A and family B GPCRs. Science 2020 Jul 31;369(6503)

Date

08/01/2020

Pubmed ID

32732395

Pubmed Central ID

PMC7954662

DOI

10.1126/science.aba3373

Scopus ID

2-s2.0-85088884640 (requires institutional sign-in at Scopus site)   84 Citations

Abstract

Family B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-G_s protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β₂ adrenergic receptor (β₂AR; family A). We determined the structure of the GCGR-G_s complex by means of cryo-electron microscopy at 3.1-angstrom resolution. This structure shows the distinct break in TM6. Guanosine triphosphate (GTP) turnover, guanosine diphosphate release, GTP binding, and G protein dissociation studies revealed much slower rates for G protein activation by the GCGR compared with the β₂AR. Fluorescence and double electron-electron resonance studies suggest that this difference is due to the inability of agonist alone to induce a detectable outward movement of the cytoplasmic end of TM6.

Author List

Hilger D, Kumar KK, Hu H, Pedersen MF, O'Brien ES, Giehm L, Jennings C, Eskici G, Inoue A, Lerch M, Mathiesen JM, Skiniotis G, Kobilka BK

Author

Michael Lerch PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cryoelectron Microscopy
Enzyme Activation
GTP-Binding Protein alpha Subunits, Gs
Humans
Protein Structure, Secondary
Receptors, Adrenergic, beta-2
Receptors, Glucagon