Open AccessGPCR large-amplitude dynamics by 19 F-NMR of aprepitant bound to the neurokinin 1 receptor
Author(s) -
Benxun Pan,
Dongsheng Li,
Lingyun Yang,
Kurt Wüthrich
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2122682119
Subject(s) - aprepitant , g protein coupled receptor , ligand (biochemistry) , chemistry , stereochemistry , transmembrane domain , receptor , biophysics , biochemistry , biology , genetics , chemotherapy , antiemetic
Significance G protein-coupled receptor (GPCR) structures determined by X-ray crystallography or cryo-electron microscopy include 28 receptors for which complexes with agonists and antagonists can be compared. In all these comparisons, an interatomic distance representing the size of the orthosteric ligand binding groove differs by less than 2.9 Å. In this report,19 F-NMR observations of the NK1R-bound drug molecule aprepitant show that the orthosteric binding groove undergoes transient fluctuations with amplitudes 6 to 8 Å. We propose that this large-amplitude plasticity enables a multistep selection of functional ligands with variable efficacies. These insights into structural dynamics also provide a rationale for the observation that diffracting crystals are obtained for GPCR complexes with only few of the ligands that bind to the receptors.