International research, led by a team at Trinity College Dublin, has revealed how the thromboxane A₂ receptor (TP) is activated, providing a clearer understanding of a clinically important pathway and informing future drug development for heart and lung diseases.

The G protein-coupled TP plays a central role in platelet aggregation, vascular tone and inflammatory processes, but has been difficult to study because its natural ligand is highly unstable, with a half-life of around 30 seconds.

In a study published in the journal Nature Communications, researchers used cryo-electron microscopy to determine the high-resolution structure of the human TPα receptor isoform in its active state, bound to the stable thromboxane mimetics U46619 and I-BOP, enabling detailed structural and functional analysis.

Functional assays confirmed that both compounds were highly potent at the receptor, with half-maximal effective concentration values of 11.22 nM for U46619 and 1.79 nM for I-BOP. Structural analysis showed that both molecules bind deep within the receptor, adopt a similar conformation and trigger activation.

The work provides new details on how the receptor is switched on. Rather than relying on the classical activation mechanism seen in many similar G protein-coupled receptors, TP appeared to use a distinct pathway involving key structural changes within the receptor that enable downstream signalling.

The findings also suggest that activating molecules may access the receptor through the surrounding membrane, rather than exclusively from outside the cell.

Implications of TP activation for drug development

The researchers also linked these findings to known disease-associated receptor variants. Certain mutations were shown to substantially reduce receptor activity by up to 10–200-fold, helping to explain inherited platelet disorders and bleeding tendencies.

Lead author, Dr Pawel Krawinski, a postdoctoral research fellow at Trinity College’s Schools of Medicine, and Biochemistry and Immunology, said: ‘These insights are fascinating to us, but they are far more than just structural details as they could have important medical implications too.

‘The thromboxane receptor plays a role in multiple diseases, including cardiovascular and cardiopulmonary disorders, pulmonary arterial hypertension, and fibrotic lung disease. It is also overactive in some cancers and inflammatory conditions.

‘By revealing exactly how activating molecules bind and trigger the receptor, the new molecular map provides a blueprint for developing drugs that can selectively block or fine-tune its activity.’

The authors noted that some aspects of receptor activation, particularly how ligands enter the binding site, remain model-based and require further confirmation. However, the study provided a clearer structural framework for understanding TP function.

While the findings do not have immediate implications for clinical practice, they improve understanding of a key therapeutic target and may support the development of more selective treatments for certain respiratory, cardiopulmonary and bleeding conditions, they concluded.

Reference
Krawinski P et al. Structural and dynamic insights into agonist recognition and function of the thromboxane A2 receptor. Nat Commun 2026;17:3071.