6WPW

GCGR-Gs signaling complex bound to a designed glucagon derivative

Summary for 6WPW

• Entry DOI: 10.2210/pdb6wpw/pdb
• EMDB information: 21866
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, g protein, glucagon, signaling, complex, signaling protein-hormone-immune system complex, signaling protein/hormone/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 166540.70

Authors

Hilger, D.,Krishna Kumar, K.,Hu, H.,Mathiesen, J.M.,Skiniotis, G.,Kobilka, B.K. (deposition date: 2020-04-28, release date: 2020-08-12, Last modification date: 2024-10-30)

Primary citation

Hilger, D.,Kumar, K.K.,Hu, H.,Pedersen, M.F.,O'Brien, E.S.,Giehm, L.,Jennings, C.,Eskici, G.,Inoue, A.,Lerch, M.,Mathiesen, J.M.,Skiniotis, G.,Kobilka, B.K.
Structural insights into differences in G protein activation by family A and family B GPCRs.
Science, 369:-, 2020

PubMed 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 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 β adrenergic receptor (βAR; family A). We determined the structure of the GCGR-G 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 βAR. 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.

PubMed: 32732395
DOI: 10.1126/science.aba3373

Experimental method

ELECTRON MICROSCOPY (3.1 Å)