Structure and dynamics of the CGRP receptor in apo and peptide-bound forms

Tracy M. Josephs, Matthew J. Belousoff, Yi Lynn Liang, Sarah J. Piper, Jianjun Cao, Daniel J. Garama, Katie Leach, Karen J. Gregory, Arthur Christopoulos, Debbie L. Hay, Radostin Danev, Denise Wootten, Patrick M. Sexton

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene-related peptide (CGRP) receptors from insect cells to determine their cryo-electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.

Original languageEnglish
Article numbereabf7258
Number of pages11
JournalScience
Volume372
Issue number6538
DOIs
Publication statusPublished - 9 Apr 2021

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