Abstract
Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.
| Original language | English |
|---|---|
| Pages (from-to) | 492-497 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 561 |
| Issue number | 7724 |
| DOIs | |
| Publication status | Published - 27 Sep 2018 |
Cite this
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Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. / Liang, Yi-Lynn; Khoshouei, Maryam; Deganutti, Giuseppe; Glukhova, Alisa; Koole, Cassandra; Peat, Thomas S.; Radjainia, Mazdak; Plitzko, Jürgen M.; Baumeister, Wolfgang; Miller, Laurence J.; Hay, Deborah L.; Christopoulos, Arthur; Reynolds, Christopher A.; Wootten, Denise; Sexton, Patrick M.
In: Nature, Vol. 561, No. 7724, 27.09.2018, p. 492-497.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor
AU - Liang, Yi-Lynn
AU - Khoshouei, Maryam
AU - Deganutti, Giuseppe
AU - Glukhova, Alisa
AU - Koole, Cassandra
AU - Peat, Thomas S.
AU - Radjainia, Mazdak
AU - Plitzko, Jürgen M.
AU - Baumeister, Wolfgang
AU - Miller, Laurence J.
AU - Hay, Deborah L.
AU - Christopoulos, Arthur
AU - Reynolds, Christopher A.
AU - Wootten, Denise
AU - Sexton, Patrick M.
PY - 2018/9/27
Y1 - 2018/9/27
N2 - Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.
AB - Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.
UR - http://www.scopus.com/inward/record.url?scp=85054098142&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0535-y
DO - 10.1038/s41586-018-0535-y
M3 - Article
VL - 561
SP - 492
EP - 497
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7724
ER -