8FLU

Human PTH1R in complex with LA-PTH and Gs

8FLU の概要

• エントリーDOI: 10.2210/pdb8flu/pdb
• EMDBエントリー: 29283 29284 29285 29286 29287
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: gpcr, agonist, hormone, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 177195.87

構造登録者

Cary, B.P.,Belousoff, M.J.,Piper, S.J.,Wootten, D.,Sexton, P.M. (登録日: 2022-12-22, 公開日: 2023-04-26, 最終更新日: 2024-10-16)

主引用文献

Cary, B.P.,Gerrard, E.J.,Belousoff, M.J.,Fletcher, M.M.,Jiang, Y.,Russell, I.C.,Piper, S.J.,Wootten, D.,Sexton, P.M.
Molecular insights into peptide agonist engagement with the PTH receptor.
Structure, 31:668-676.e5, 2023

PubMed Abstract: The parathyroid hormone (PTH) 1 receptor (PTH1R) is a G protein-coupled receptor (GPCR) that regulates skeletal development and calcium homeostasis. Here, we describe cryo-EM structures of the PTH1R in complex with fragments of the two hormones, PTH and PTH-related protein, the drug abaloparatide, as well as the engineered tool compounds, long-acting PTH (LA-PTH) and the truncated peptide, M-PTH(1-14). We found that the critical N terminus of each agonist engages the transmembrane bundle in a topologically similar fashion, reflecting similarities in measures of Gαs activation. The full-length peptides induce subtly different extracellular domain (ECD) orientations relative to the transmembrane domain. In the structure bound to M-PTH, the ECD is unresolved, demonstrating that the ECD is highly dynamic when unconstrained by a peptide. High resolutions enabled identification of water molecules near peptide and G protein binding sites. Our results illuminate the action of orthosteric agonists of the PTH1R.

PubMed: 37148874
DOI: 10.1016/j.str.2023.04.002

実験手法

ELECTRON MICROSCOPY (2.76 Å)