期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 10, 页码 1096-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0567-0
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Disease
- National Institute of General Medical Sciences
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute on Drug Abuse of the US National Institutes of Health [R01-DK111427, R01-DK116780, R01-DK122259, DK011794, P41-GM103712, P30-DA035778, R01-DA046939, F31-AR074843]
Peptide ligands of class B G-protein-coupled receptors act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor-arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that initial binding of the PTH C-terminal part constrains the conformation of the flexible PTH N-terminal signaling epitope before a second binding event occurs. A 'hot-spot' PTH residue, His9, that inserts into the PTHR transmembrane domain at this second step allosterically engages receptor-arrestin coupling. A conformational change in PTHR intracellular loop 3 permits favorable interactions with beta-arrestin's finger loop. These results unveil structural determinants for PTHR-arrestin complex formation and reveal that the two-step binding mechanism proceeds via cooperative fluctuations between ligand and receptor, which extend to other class B G-protein-coupled receptors. Characterization of the interaction between PTH and its G-protein-coupled receptor, PTHR, shows conformational changes coupled to residues interacting with His9, which helps position the PTH N terminus at the PTHR transmembrane domain to facilitate beta-arrestin coupling.
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