Ligand entry pathways control the chemical space recognized by GPR183

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• dc.contributor.author Kjaer, Viktoria Madeline Skovgaard
• dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
• dc.contributor.author Medel Lacruz, Brian
• dc.contributor.author Reinmuth, Lisa
• dc.contributor.author Ciba, Marija
• dc.contributor.author Rexen Ulven, Elisabeth
• dc.contributor.author Bonomi, Massimiliano
• dc.contributor.author Selent, Jana
• dc.contributor.author Rosenkilde, Mette Marie
• dc.date.accessioned 2024-05-02T05:49:48Z
• dc.date.available 2024-05-02T05:49:48Z
• dc.date.issued 2023
• dc.description.abstract The G protein-coupled receptor GPR183 is a chemotactic receptor with an important function in the immune system and association with a variety of diseases. It recognizes ligands with diverse physicochemical properties as both the endogenous oxysterol ligand 7α,25-OHC and synthetic molecules can activate the G protein pathway of the receptor. To better understand the ligand promiscuity of GPR183, we utilized both molecular dynamics simulations and cell-based validation experiments. Our work reveals that the receptor possesses two ligand entry channels: one lateral between transmembrane helices 4 and 5 facing the membrane, and one facing the extracellular environment. Using enhanced sampling, we provide a detailed structural model of 7α,25-OHC entry through the lateral membrane channel. Importantly, the first ligand recognition point at the receptor surface has been captured in diverse experimentally solved structures of different GPCRs. The proposed ligand binding pathway is supported by in vitro data employing GPR183 mutants with a sterically blocked lateral entrance, which display diminished binding and signaling. In addition, computer simulations and experimental validation confirm the existence of a polar water channel which might serve as an alternative entrance gate for less lipophilic ligands from the extracellular milieu. Our study reveals knowledge to understand GPR183 functionality and ligand recognition with implications for the development of drugs for this receptor. Beyond, our work provides insights into a general mechanism GPCRs may use to respond to chemically diverse ligands.
• dc.format.mimetype application/pdf
• dc.identifier.citation Kjær VMS, Stępniewski TM, Medel-Lacruz B, Reinmuth L, Ciba M, Rexen Ulven E, et al. Ligand entry pathways control the chemical space recognized by GPR183. Chem Sci. 2023 Sep 25;14(39):10671-83. DOI: 10.1039/d2sc05962b
• dc.identifier.doi http://dx.doi.org/10.1039/d2sc05962b
• dc.identifier.issn 2041-6520
• dc.identifier.uri http://hdl.handle.net/10230/59964
• dc.language.iso eng
• dc.publisher Royal Society of Chemistry
• dc.relation.ispartof Chem Sci. 2023 Sep 25;14(39):10671-83
• dc.rights © 2023 The Author(s). Published by the Royal Society of Chemistry. This Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence (https://creativecommons.org/licenses/by-nc/3.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/3.0/
• dc.subject.other Dinàmica molecular
• dc.subject.other Proteïnes G
• dc.title Ligand entry pathways control the chemical space recognized by GPR183
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion