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TitleNegative allosteric modulation of the glucagon receptor by RAMP2.
Journal, issue, pagesCell, Vol. 186, Issue 7, Page 1465-1477.e18, Year 2023
Publish dateMar 30, 2023
AuthorsKaavya Krishna Kumar / Evan S O'Brien / Chris H Habrian / Naomi R Latorraca / Haoqing Wang / Inga Tuneew / Elizabeth Montabana / Susan Marqusee / Daniel Hilger / Ehud Y Isacoff / Jesper Mosolff Mathiesen / Brian K Kobilka /
PubMed AbstractReceptor 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 ...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.
External linksCell / PubMed:37001505 / PubMed Central
MethodsEM (single particle)
Resolution2.9 Å
Structure data

EMDB-29453, PDB-8fu6:
GCGR-Gs complex in the presence of RAMP2
Method: EM (single particle) / Resolution: 2.9 Å

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN / G-protein coupled receptor / RAMP / G-protein / Gs / Nb35 / GPCR / glucagon receptor / glucagon / peptide agonist

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