دورية أكاديمية
Deciphering specificity and cross-reactivity in tachykinin NK1 and NK2 receptors.
| العنوان: | Deciphering specificity and cross-reactivity in tachykinin NK1 and NK2 receptors. |
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| المؤلفون: | Madsen JJ; Global and Planetary Health, College of Public Health, University of South Florida, Tampa, Florida, USA; Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA., Petersen JE; Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Christensen DP; Embark Biotech ApS, Copenhagen, Denmark., Hansen JB; Embark Biotech ApS, Copenhagen, Denmark., Schwartz TW; Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Frimurer TM; Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Olsen OH; Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. Electronic address: oho@sund.ku.dk. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2023 Dec; Vol. 299 (12), pp. 105438. Date of Electronic Publication: 2023 Nov 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Receptors, Neurokinin-1*/agonists , Receptors, Neurokinin-1*/metabolism , Tachykinins*/metabolism, Animals ; Humans ; Cell Line ; Chlorocebus aethiops ; Ligands ; Neurokinin A/metabolism ; Neurokinin-1 Receptor Antagonists ; Substance P ; Receptors, Neurokinin-2/metabolism |
| مستخلص: | 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. Competing Interests: Conflict of interest D. P. C. and J. B. H. are employees of Embark Biotech ApS. All other authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: G protein-coupled receptor (GPCR); cross-reactivity; molecular dynamics; molecular modeling; mutagenesis; peptide interaction |
| المشرفين على المادة: | 0 (Ligands) 86933-74-6 (Neurokinin A) 0 (Neurokinin-1 Receptor Antagonists) 0 (Receptors, Neurokinin-1) 33507-63-0 (Substance P) 0 (Tachykinins) 0 (TAC1 protein, human) 0 (Receptors, Neurokinin-2) |
| تواريخ الأحداث: | Date Created: 20231109 Date Completed: 20240102 Latest Revision: 20240624 |
| رمز التحديث: | 20240624 |
| مُعرف محوري في PubMed: | PMC10724690 |
| DOI: | 10.1016/j.jbc.2023.105438 |
| PMID: | 37944618 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2023.105438 |