Ligand entry pathways control the chemical space recognized by GPR183

Research output: Contribution to journalJournal articlepeer-review

Standard

Ligand entry pathways control the chemical space recognized by GPR183. / Kjær, Viktoria Madeline Skovgaard; Stępniewski, Tomasz Maciej; Medel-Lacruz, Brian; Reinmuth, Lisa; Ciba, Marija; Rexen Ulven, Elisabeth; Bonomi, Massimiliano; Selent, Jana; Rosenkilde, Mette Marie.

In: Chemical Science, Vol. 14, No. 39, 2023, p. 10671-10683.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Kjær, VMS, Stępniewski, TM, Medel-Lacruz, B, Reinmuth, L, Ciba, M, Rexen Ulven, E, Bonomi, M, Selent, J & Rosenkilde, MM 2023, 'Ligand entry pathways control the chemical space recognized by GPR183', Chemical Science, vol. 14, no. 39, pp. 10671-10683. https://doi.org/10.1039/d2sc05962b

APA

Kjær, V. M. S., Stępniewski, T. M., Medel-Lacruz, B., Reinmuth, L., Ciba, M., Rexen Ulven, E., Bonomi, M., Selent, J., & Rosenkilde, M. M. (2023). Ligand entry pathways control the chemical space recognized by GPR183. Chemical Science, 14(39), 10671-10683. https://doi.org/10.1039/d2sc05962b

Vancouver

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. Chemical Science. 2023;14(39):10671-10683. https://doi.org/10.1039/d2sc05962b

Author

Kjær, Viktoria Madeline Skovgaard ; Stępniewski, Tomasz Maciej ; Medel-Lacruz, Brian ; Reinmuth, Lisa ; Ciba, Marija ; Rexen Ulven, Elisabeth ; Bonomi, Massimiliano ; Selent, Jana ; Rosenkilde, Mette Marie. / Ligand entry pathways control the chemical space recognized by GPR183. In: Chemical Science. 2023 ; Vol. 14, No. 39. pp. 10671-10683.

Bibtex

@article{bdac90e12b564b51b7e0ee1c6d952c75,
title = "Ligand entry pathways control the chemical space recognized by GPR183",
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.",
author = "Kj{\ae}r, {Viktoria Madeline Skovgaard} and St{\c e}pniewski, {Tomasz Maciej} and Brian Medel-Lacruz and Lisa Reinmuth and Marija Ciba and {Rexen Ulven}, Elisabeth and Massimiliano Bonomi and Jana Selent and Rosenkilde, {Mette Marie}",
note = "Publisher Copyright: {\textcopyright} 2023 The Royal Society of Chemistry.",
year = "2023",
doi = "10.1039/d2sc05962b",
language = "English",
volume = "14",
pages = "10671--10683",
journal = "Chemical Science",
issn = "2041-6520",
publisher = "Royal Society of Chemistry",
number = "39",

}

RIS

TY - JOUR

T1 - Ligand entry pathways control the chemical space recognized by GPR183

AU - Kjær, Viktoria Madeline Skovgaard

AU - Stępniewski, Tomasz Maciej

AU - Medel-Lacruz, Brian

AU - Reinmuth, Lisa

AU - Ciba, Marija

AU - Rexen Ulven, Elisabeth

AU - Bonomi, Massimiliano

AU - Selent, Jana

AU - Rosenkilde, Mette Marie

N1 - Publisher Copyright: © 2023 The Royal Society of Chemistry.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1039/d2sc05962b

DO - 10.1039/d2sc05962b

M3 - Journal article

C2 - 37829039

AN - SCOPUS:85173703366

VL - 14

SP - 10671

EP - 10683

JO - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 39

ER -

ID: 370475089