Deciphering specificity and cross-reactivity in tachykinin NK1 and NK2 receptors
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 3,05 MB, PDF-dokument
The tachykinin receptors neurokinin 1 (NK1R) and neurokinin 2 (NK2R) are G protein-coupled receptors that bind preferentially to the natural peptide ligands substance P and neurokinin A, respectively, and have been targets for drug development. Despite sharing a common C-terminal sequence of Phe-X-Gly-Leu-Met-NH2 that helps direct biological function, the peptide ligands exhibit some degree of cross-reactivity toward each other's non-natural receptor. Here, we investigate the detailed structure–activity relationships of the ligand-bound receptor complexes that underlie both potent activation by the natural ligand and cross-reactivity. We find that the specificity and cross-reactivity of the peptide ligands can be explained by the interactions between the amino acids preceding the FxGLM consensus motif of the bound peptide ligand and two regions of the receptor: the β-hairpin of the extracellular loop 2 (ECL2) and a N-terminal segment leading into transmembrane helix 1. Positively charged sidechains of the ECL2 (R177 of NK1R and K180 of NK2R) are seen to play a vital role in the interaction. The N-terminal positions 1 to 3 of the peptide ligand are entirely dispensable. Mutated and chimeric receptor and ligand constructs neatly swap around ligand specificity as expected, validating the structure-activity hypotheses presented. These findings will help in developing improved agonists or antagonists for NK1R and NK2R.
Originalsprog | Engelsk |
---|---|
Artikelnummer | 105438 |
Tidsskrift | Journal of Biological Chemistry |
Vol/bind | 299 |
Udgave nummer | 12 |
Antal sider | 11 |
ISSN | 0021-9258 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Dr Pan Shi and co-workers for providing the coordinates and density data of the NK2R:NKA cryo-EM structure from their study prior to its scheduled release in the Protein Data Bank (PDB ID: 7xwo). Elizabeth L. Lansbury is thanked for proofreading the manuscript. O. H. O. conceptualization; J. E. P. D. P. C. J. B. H. and O. H. O. investigation; J. E. P. D. P. C. J. B. H. O. H. O. and J. J. M. analysis and interpretation; J. J. M. and O. H. O. writing–original draft; J. J. M. and O. H. O. writing–review & editing.
Publisher Copyright:
© 2023 The Authors
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 378806219