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Structural biology

Insights into platelet pharmacology from a cryo-EM structure of the ABCC4 transporter

Nature Cardiovascular Research volume 2, pages 606–608 (2023)Cite this article

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Structural determination of the ABCC4 transporter is a major first step in providing crucial molecular insights into the transport of platelet substrates into granules, as well as drug transport from platelets. The findings provide a framework for understanding platelet interactions and potential design of specific platelet antagonists.

The use of low-dose aspirin as an antiplatelet agent in the treatment and secondary prevention of adverse thrombotic cardiovascular events (such as acute coronary syndromes and strokes) was one of the most important public health achievements of the twentieth century1. Development of other antiplatelet agents quickly followed, including phosphodiesterase and adenine deaminase inhibitors (such as dipyridamole), ADP-receptor P2Y12 antagonists (ticlopidine and clopidogrel), PAR1 antagonists (vorapaxor), and GPIIb/IIIa inhibitors (abciximab and eftifibatide)2. With the increasing repertoire of antiplatelet agents, issues have emerged including excessive bleeding, drug–drug interactions, and pharmacological resistance or insensitivity3,4. A molecular understanding of platelet pharmacodynamics and pharmacokinetics for platelet substrates and targeted drugs is needed.

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Fig. 1: Proposed mechanism of ABCC4-mediated transport of platelet substrates and inhibitors.
Fig. 2: Competitive inhibition of ABCC4-mediated aspirin transport by dipyridamole.

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Acknowledgements

This work was funded by National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) (R01-HL122815, R01-HL150515 and R01-HL115247) to J.H., a K08 award to A.S. (K08-HL150246), and a T32 to S.X.G. (T32-HL007974).

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Authors and Affiliations

  1. Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Anish V. Sharda

  2. Department of Laboratory Medicine, Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT, USA

    Sean X. Gu

  3. Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    John Hwa

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  1. Anish V. Sharda
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  2. Sean X. Gu
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  3. John Hwa
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Correspondence to John Hwa.

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Sharda, A.V., Gu, S.X. & Hwa, J. Insights into platelet pharmacology from a cryo-EM structure of the ABCC4 transporter. Nat Cardiovasc Res 2, 606–608 (2023). https://doi.org/10.1038/s44161-023-00293-z

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