Structural basis of ligand recognition and design of antihistamines targeting histamine H 4 receptor.

Autor: Xia R; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Shi S; Department of Medicinal Chemistry, Amsterdam Institute for Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HV, Amsterdam, The Netherlands., Xu Z; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Vischer HF; Department of Medicinal Chemistry, Amsterdam Institute for Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HV, Amsterdam, The Netherlands., Windhorst AD; Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands., Qian Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Duan Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Liang J; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Chen K; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Zhang A; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Guo C; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Leurs R; Department of Medicinal Chemistry, Amsterdam Institute for Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HV, Amsterdam, The Netherlands. r.leurs@vu.nl., He Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. ajian.he@hit.edu.cn.; Frontiers Science Center for Matter Behave in Space Environment, Harbin Institute of Technology, Harbin, China. ajian.he@hit.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 20; Vol. 15 (1), pp. 2493. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1038/s41467-024-46840-5
Abstrakt: The histamine H 4 receptor (H 4 R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H 4 R remains elusive. Here, we report four cryo-EM structures of H 4 R/G i complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D94 3.32 and a π-π network determine the orientation of the positively charged group of ligands, while E182 5.46 , located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H 4 R ligand binding allows us to identify mutants at E182 5.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and G i engagement, we establish a framework for understanding H 4 R signaling and provide a rational basis for designing novel antihistamines targeting H 4 R.
(© 2024. The Author(s).)
Databáze: MEDLINE
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