Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

Yi-Lynn Liang, Maryam Khoshouei, Giuseppe Deganutti, Alisa Glukhova, Cassandra Koole, Thomas S. Peat, Mazdak Radjainia, Jürgen M. Plitzko, Wolfgang Baumeister, Laurence J. Miller, Deborah L. Hay, Arthur Christopoulos, Christopher A. Reynolds, Denise Wootten () and Patrick M. Sexton ()
Additional contact information
Yi-Lynn Liang: Monash Institute of Pharmaceutical Sciences, Monash University
Maryam Khoshouei: Max Planck Institute of Biochemistry
Giuseppe Deganutti: School of Biological Sciences, University of Essex
Alisa Glukhova: Monash Institute of Pharmaceutical Sciences, Monash University
Cassandra Koole: Monash Institute of Pharmaceutical Sciences, Monash University
Thomas S. Peat: CSIRO Biomedical Manufacturing
Mazdak Radjainia: Monash Institute of Pharmaceutical Sciences, Monash University
Jürgen M. Plitzko: Max Planck Institute of Biochemistry
Wolfgang Baumeister: Max Planck Institute of Biochemistry
Laurence J. Miller: Monash Institute of Pharmaceutical Sciences, Monash University
Deborah L. Hay: University of Auckland
Arthur Christopoulos: Monash Institute of Pharmaceutical Sciences, Monash University
Christopher A. Reynolds: School of Biological Sciences, University of Essex
Denise Wootten: Monash Institute of Pharmaceutical Sciences, Monash University
Patrick M. Sexton: Monash Institute of Pharmaceutical Sciences, Monash University

Nature, 2018, vol. 561, issue 7724, 492-497

Abstract: 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.

Keywords: Calcitonin Gene-related Peptide (CGRP); CGRP Receptor; Receptor Activity-modifying Proteins (RAMP1); Lauryl Maltose Neopentyl Glycol (LMNG); Receptor Core (search for similar items in EconPapers)
Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0535-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:561:y:2018:i:7724:d:10.1038_s41586-018-0535-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0535-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().