National Health and Medical Research Council (NHMRC, Australia)
1061044
Australia
National Health and Medical Research Council (NHMRC, Australia)
1055134
Australia
National Health and Medical Research Council (NHMRC, Australia)
1065410
Australia
National Health and Medical Research Council (NHMRC, Australia)
1126857
Australia
Citation
Journal: ACS Pharmacol Transl Sci / Year: 2019 Title: The Molecular Control of Calcitonin Receptor Signaling. Authors: Emma Dal Maso / Alisa Glukhova / Yue Zhu / Javier Garcia-Nafria / Christopher G Tate / Silvia Atanasio / Christopher A Reynolds / Erney Ramírez-Aportela / Jose-Maria Carazo / Caroline A ...Authors: Emma Dal Maso / Alisa Glukhova / Yue Zhu / Javier Garcia-Nafria / Christopher G Tate / Silvia Atanasio / Christopher A Reynolds / Erney Ramírez-Aportela / Jose-Maria Carazo / Caroline A Hick / Sebastian G B Furness / Debbie L Hay / Yi-Lynn Liang / Laurence J Miller / Arthur Christopoulos / Ming-Wei Wang / Denise Wootten / Patrick M Sexton / Abstract: The calcitonin receptor (CTR) is a class B G protein-coupled receptor (GPCR) that responds to the peptide hormone calcitonin (CT). CTs are clinically approved for the treatment of bone diseases. We ...The calcitonin receptor (CTR) is a class B G protein-coupled receptor (GPCR) that responds to the peptide hormone calcitonin (CT). CTs are clinically approved for the treatment of bone diseases. We previously reported a 4.1 Å structure of the activated CTR bound to salmon CT (sCT) and heterotrimeric Gs protein by cryo-electron microscopy (Liang, Y.-L., . Phase-plate cryo- EM structure of a class B GPCR-G protein complex. , , 118-123). In the current study, we have reprocessed the electron micrographs to yield a 3.3 Å map of the complex. This has allowed us to model extracellular loops (ECLs) 2 and 3, and the peptide N-terminus that previously could not be resolved. We have also performed alanine scanning mutagenesis of ECL1 and the upper segment of transmembrane helix 1 (TM1) and its extension into the receptor extracellular domain (TM1 stalk), with effects on peptide binding and function assessed by cAMP accumulation and ERK1/2 phosphorylation. These data were combined with previously published alanine scanning mutagenesis of ECL2 and ECL3 and the new structural information to provide a comprehensive 3D map of the molecular surface of the CTR that controls binding and signaling of distinct CT and related peptides. The work highlights distinctions in how different, related, class B receptors may be activated. The new mutational data on the TM1 stalk and ECL1 have also provided critical insights into the divergent control of cAMP versus pERK signaling and, collectively with previous mutagenesis data, offer evidence that the conformations linked to these different signaling pathways are, in many ways, mutually exclusive. This study furthers our understanding of the complex nature of signaling elicited by GPCRs and, in particular, that of the therapeutically important class B subfamily.
History
Deposition
Jan 2, 2019
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Header (metadata) release
Jan 23, 2019
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Map release
Jan 23, 2019
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Update
Apr 8, 2020
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Current status
Apr 8, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : Complex of a full-length, active-state calcitonin receptor with p...
Entire
Name: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35
Components
Complex: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35
Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Protein or peptide: Nanobody35
Protein or peptide: Calcitonin receptor
Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Protein or peptide: Calcitonin
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Supramolecule #1: Complex of a full-length, active-state calcitonin receptor with p...
Supramolecule
Name: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)
Organism: Homo sapiens (human)
Recombinant expression
Organism: Trichoplusia ni (cabbage looper)
Molecular weight
Theoretical: 150 KDa
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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule
Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
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