ArticleProceedings of the National Academy of Sciences of the United States of America2022
GPCR large-amplitude dynamics by
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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Who cites it
13 citing papers in PubMed, 32 citations in OpenAlex.
- Detection of an Antagonist Bound to the Neurokinin a Receptor in Styrene-Maleic Acid Lipid Particles byChembiochem : a European journal of chemical biology · 2026Article
- Human Substance P Interactions with G Protein-Coupled Receptor NK1R Observed by NMR in Solution.Journal of the American Chemical Society · 2025Article
- The Allosteric Mechanism of G-Protein-Coupled Receptors is Induced Fit, Not Conformational Selection.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Rational design ofNature communications · 2025Article
- Bisecting GlcNAc modification reverses the chemoresistance via attenuating the function of P-gp.Theranostics · 2024Article
- Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1.Nature communications · 2023Article
- The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant.International journal of molecular sciences · 2023Review
- Solution NMR investigations of integral membrane proteins: Challenges and innovations.Current opinion in structural biology · 2023Review
- Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor AMolecules (Basel, Switzerland) · 2023Article
- Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR.iScience · 2023Article
- Allosteric coupling between G-protein binding and extracellular ligand binding sites in GPR52 revealed byMedComm · 2023Article
- Assessing the applicability ofJournal of biomolecular NMR · 2023Article
- G Protein-coupled Receptor (GPCR) Reconstitution and Labeling for Solution Nuclear Magnetic Resonance (NMR) Studies of the Structural Basis of Transmembrane Signaling.Molecules (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.