Zhang Haitao's research group at the School of Pharmacy of Zhejiang University reported in Nature Communications that the drug target histamine H3...

Histamine is an endogenous biogenic amine that acts on G protein-coupled receptors (GPCRs).
Four different histamine receptors (H1R, H2R, H3R, H4R) in the family mediate a variety of physiological and pathological processes.

Histamine H1 receptors (H1R) and histamine H2 receptors (H2R) are associated with allergic reactions and gastric acid secretion, respectively, while histamine H4 The receptor (H4R) is mainly involved in the body's immune response
.
Histamine H3 receptors (H3R) are mainly found on histaminergic neurons in the brain and are associated with sleep, wakefulness, learning and memory, appetite, and cerebral ischemic physiological processes, making them potentially important drug targets for the treatment of sleep disorders, Alzheimer's disease, schizophrenia, myocardial ischemia, and obesity
。 At present, only Pitolisant among H3R antagonists is approved for the treatment of drowsiness, and most antagonists have been terminated in clinical trials due to side effects such as cardiotoxicity and phospholipidosis, so it is necessary to optimize and design new targeted H3R drugs
.

On October 15, 2022, the research team of Zhang Haitao from the School of Pharmacy of Zhejiang University published a publication entitled " Structural basis for recognition of antihistamine drug by human histamine receptor"
.
In this study, the crystal structure of the complex of human histamine receptor H3R and antagonist PF-03654746 was analyzed by protein crystallography, and the antagonist PF-03654746 was systematically elucidated by combining computational and functional experimental results The unique binding mode of allosteric regulation of molecular cholesterol and the conserved binding mode of different antagonists provide a structural basis
for the design of H3R-based drugs.

Using protein crystallography, the research team resolved 2.
6? Crystal structure of the complex of H3R with antagonist PF-03654746.

PF-03654746 was found to occupy a relatively narrow ligand-binding pocket, and near the extracellular fraction there was an extended binding pocket consisting of TM2, TM7, and ECL2, and molecular docking elucidated Conservative binding mode
of H3R antagonists.
In the H3R structure, a cholesterol molecule is found to bind between TM1 and TM7, and the binding of this molecule contributes to ligand binding and affects receptor conformation through hydrophobic and electrostatic
interactions.
Further comparison with the known H1R structure revealed the structural mechanism
of H3R antagonism.

Molecular mechanism by which PF-03654746 and cholesterol act on H3R

Molecular mechanisms by which different antagonists act on H3R

The first author of this paper is Peng Xueqian, a doctoral student at the School of Pharmacy, Zhejiang University, and the corresponding author is Zhang Haitao, a researcher
at the School of Pharmacy, Zhejiang University.
Professor Chen Zhong of Zhejiang University of Traditional Chinese Medicine, Professor Yang Linlin of Zhengzhou University, and researcher Qin Wenming of Shanghai Synchrotron Radiation Source respectively provided great help for
the functional analysis, computational analysis and crystal X-ray diffraction data collection of this study.
This project is supported
by the National Key Research and Development Program, the National Science and Technology Major Project, and the National Natural Science Foundation of China.

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