8FU6

GCGR-Gs complex in the presence of RAMP2

Summary for 8FU6

• Entry DOI: 10.2210/pdb8fu6/pdb
• EMDB information: 29453
• 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: g-protein coupled receptor, ramp, g-protein, gs, nb35, gpcr, glucagon receptor, glucagon, peptide agonist, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 166540.70

Authors

Krishna Kumar, K.,O'Brien, E.S.,Wang, H.,Montabana, E.,Kobilka, B.K. (deposition date: 2023-01-16, release date: 2023-04-12, Last modification date: 2024-11-06)

Primary citation

Krishna Kumar, K.,O'Brien, E.S.,Habrian, C.H.,Latorraca, N.R.,Wang, H.,Tuneew, I.,Montabana, E.,Marqusee, S.,Hilger, D.,Isacoff, E.Y.,Mathiesen, J.M.,Kobilka, B.K.
Negative allosteric modulation of the glucagon receptor by RAMP2.
Cell, 186:1465-1477.e18, 2023

PubMed Abstract: Receptor activity-modifying proteins (RAMPs) modulate the activity of many Family B GPCRs. We show that RAMP2 directly interacts with the glucagon receptor (GCGR), a Family B GPCR responsible for blood sugar homeostasis, and broadly inhibits receptor-induced downstream signaling. HDX-MS experiments demonstrate that RAMP2 enhances local flexibility in select locations in and near the receptor extracellular domain (ECD) and in the 6 transmembrane helix, whereas smFRET experiments show that this ECD disorder results in the inhibition of active and intermediate states of the intracellular surface. We determined the cryo-EM structure of the GCGR-G complex at 2.9 Å resolution in the presence of RAMP2. RAMP2 apparently does not interact with GCGR in an ordered manner; however, the receptor ECD is indeed largely disordered along with rearrangements of several intracellular hallmarks of activation. Our studies suggest that RAMP2 acts as a negative allosteric modulator of GCGR by enhancing conformational sampling of the ECD.

PubMed: 37001505
DOI: 10.1016/j.cell.2023.02.028

Experimental method

ELECTRON MICROSCOPY (2.9 Å)