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Structural Characte...
Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling
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- Kennedy, Amanda (författare)
- Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
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- Ballante, Flavio (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik,Jens Carlsson group
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- Johansson, Johan (författare)
- Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
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- Milligan, Graeme (författare)
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow
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- Sundström, Linda (författare)
- Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
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- Nordqvist, Anneli (författare)
- Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
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- Carlsson, Jens (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik,Jens Carlsson group
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(creator_code:org_t)
- 2018-10-16
- 2018
- Engelska.
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Ingår i: ACS Pharmacology & Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 1:2, s. 119-133
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://pubs.acs.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)
- NATURAL SCIENCES -- Computer and Information Sciences -- Bioinformatics (hsv//eng)
- NATURVETENSKAP -- Kemi -- Teoretisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
Nyckelord
- activation
- GPCR
- molecular docking
- orthosteric
- PAR2
- structure-based drug design
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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