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Cited by 2Drug Transport and Resistance MechanismsReceptor Mechanisms and SignalingProtein Structure and Dynamics

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Molecular basis of prostaglandin E2 reuptake by organic anion transporter PGT

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Zhu, Zhini, Li, Yaohui, Xia, Hao, Yang, Chuanhui, Zhou, Zixuan, Chao, Yulin, Ba, Qian, Li, Dianfan, Qu, Qianhui·2025·Nature Communications
DOI 10.1038/s41467-025-67025-8PMC PMC12789631

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Abstract

Abstract Prostaglandins (PGs) are bioactive lipids that regulate inflammation, reproduction, and vasopermeability. Timely clearance of excessive PGs is critical to prevent potential damages caused by prolonged signalling. The high-affinity prostaglandin transporter (PGT) plays an essential role in this termination process by efficiently re-uptaking PGs into cells. Here, we report human PGT structures in different oligomerization and substrate-binding states. Beyond the canonical MFS-fold, PGT harbours a unique cystine-rich extracellular segment that incorporates a Kazal-like domain crucial for PGT localization and activity. Two distinct PGE2-bound structures revealed essential elements for substrate recognition, elucidating a PGE2-flipping process during the multi-stop translocation cycle. Notably, PGT dimerizes in detergent micelles and lipid nanodiscs. This dimerization drastically increases the mobility of the extracellular region and induces a profound rotation of the C-domain transmembrane helices, an unprecedented observation for MFS transporters. These functionally distinct snapshots thus shed light on prostaglandin clearance and reveal uncommon features of MFS transporters.

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Metadata

Authors
Zhu, Z., Li, Y., Xia, H., Yang, C., Zhou, Z., Chao, Y., Ba, Q., Li, D., & Qu, Q.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Chinese Academy of Sciences (CN)
  • Shanghai University of Traditional Chinese Medicine (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • Li, Yaohui
  • Ba, Qian
  • Li, Dianfan
  • Qu, Qianhui
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-12-01
Volume
17
Issue
1
Pages
315-315
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-67025-8
PMC
PMC12789631
OpenAlex
W4416850979
Cited by
2
References
1
Citations by year
2026: 1 · 2025: 1
FWCI
0.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (32171194)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
prostaglandin E2, organic anion transporters, major facilitator superfamily, substrate recognition, lipid nanodiscs, detergent micelles
MeSH terms
Protein Domains, Biological Transport, Humans, Models, Molecular, Dinoprostone, Crystallography, X-Ray, Organic Anion Transporters, Protein Multimerization, HEK293 Cells

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