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Structural basis of antagonist selectivity in endothelin receptors
Junyi Hou1, Shenhui Liu2,3, Xiaodan Zhang2,3
1Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Cell Discovery
|July 29, 2024
Summary
Structural insights into endothelin receptors (ETA and ETB) reveal how drugs like macitentan and ambrisentan bind. This work provides a framework for designing new therapies for pulmonary arterial hypertension and related conditions.
Area of Science:
- Structural biology
- Pharmacology
- Molecular mechanisms of receptor activation
Background:
- Endothelins and their receptors (ETA, ETB) are crucial for vascular homeostasis.
- ETA antagonists are effective treatments for pulmonary arterial hypertension (PAH) and other cardiovascular/renal diseases.
Purpose of the Study:
- To elucidate the molecular basis of endothelin receptor binding and activation.
- To provide a structural framework for the rational design of novel endothelin receptor-targeting therapeutics.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine structures of ETA with drugs (macitentan, ambrisentan, zibotentan) and an antibody.
- Determination of active-state structures of ETA and ETB bound to endothelin-1 and an agonist (BQ3020).
Main Results:
- Detailed structures of ETA bound to PAH drugs and an antagonist.
- Identification of key residues conferring antagonist selectivity and the ETA activation mechanism.
- Epitope mapping for antibody-mediated antagonism on ETA.
Conclusions:
- The study provides a comprehensive structural understanding of endothelin receptor function and drug interactions.
- These findings facilitate the rational design of small molecules and antibodies targeting endothelin receptors for therapeutic benefit.
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