National Health and Medical Research Council (NHMRC, Australia)
1061044
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1055134
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1065410
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1126857
オーストラリア
引用
ジャーナル: ACS Pharmacol Transl Sci / 年: 2019 タイトル: The Molecular Control of Calcitonin Receptor Signaling. 著者: 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 ...著者: 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 / 要旨: 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.
全体 : Complex of a full-length, active-state calcitonin receptor with p...
全体
名称: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35
要素
複合体: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35
タンパク質・ペプチド: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
タンパク質・ペプチド: Nanobody35
タンパク質・ペプチド: Calcitonin receptor
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
タンパク質・ペプチド: Calcitonin
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超分子 #1: Complex of a full-length, active-state calcitonin receptor with p...
超分子
名称: Complex of a full-length, active-state calcitonin receptor with peptide ligand, heterotrimeric Gs protein and nanobody 35 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
由来(天然)
生物種: Homo sapiens (ヒト)
組換発現
生物種: Trichoplusia ni (イラクサキンウワバ)
分子量
理論値: 150 KDa
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分子 #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
分子
名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO