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Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.ORCID iD: 0000-0001-7650-406X
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. (Jens Carlsson group)ORCID iD: 0000-0002-4831-3423
Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow.ORCID iD: 0000-0002-6946-3519
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2018 (English)In: ACS Pharmacology & Translational Science, ISSN 2575-9108, Vol. 1, no 2, p. 119-133Article in journal (Refereed) Published
Abstract [en]

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor that is activated by proteolytic cleavage of its N-terminus. The unmasked N-terminal peptide then binds to the transmembrane bundle, leading to activation of intracellular signaling pathways associated with inflammation and cancer. Recently determined crystal structures have revealed binding sites of PAR2 antagonists, but the binding mode of the peptide agonist remains unknown. In order to generate a model of PAR2 in complex with peptide SLIGKV, corresponding to the trypsin-exposed tethered ligand, the orthosteric binding site was probed by iterative combinations of receptor mutagenesis, agonist ligand modifications and data-driven structural modeling. Flexible-receptor docking identified a conserved binding mode for agonists related to the endogenous ligand that was consistent with the experimental data and allowed synthesis of a novel peptide (1-benzyl-1H[1,2,3]triazole-4-yl-LIGKV) with higher functional potency than SLIGKV. The final model may be used to understand the structural basis of PAR2 activation and in virtual screens to identify novel PAR2 agonist and competitive antagonists. The combined experimental and computational approach to characterize agonist binding to PAR2 can be extended to study the many other G protein-coupled receptors that recognize peptides or proteins.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 1, no 2, p. 119-133
Keywords [en]
activation, GPCR, molecular docking, orthosteric, PAR2, structure-based drug design
National Category
Bioinformatics (Computational Biology) Theoretical Chemistry Organic Chemistry Medicinal Chemistry Pharmacology and Toxicology Biochemistry and Molecular Biology Structural Biology
Identifiers
URN: urn:nbn:se:uu:diva-363893DOI: 10.1021/acsptsci.8b00019OAI: oai:DiVA.org:uu-363893DiVA, id: diva2:1316273
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2019-05-22Bibliographically approved

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Kennedy, AmandaBallante, FlavioMilligan, GraemeNordqvist, AnneliCarlsson, Jens
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