Evidence map›Paper›PMID 40523902›Full record

ArticleActa pharmacologica Sinica2025

Structural characterization of the urea transporter bound to the orally bioavailable inhibitor E3.

Shen-Ming Huang, Bo-Yang Cai, Lei Liu, Le-Jin Yang, Zhi Li, Chao Zhang, Meng-Yao Xiong, Hang Zhang, Yan-Rong Li, Zhi-Zhen Huang and 3 more

Abstract read
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In one paragraph

Article in Acta pharmacologica Sinica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Shen-Ming Huang *Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China. huangshenming@jnu.edu.cn.
Bo-Yang Cai *Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China.
Lei Liu *Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Le-Jin Yang *Department of Psychology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Zhi LiJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
Chao ZhangKey Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
Meng-Yao XiongDepartment of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
Hang ZhangDepartment of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
Yan-Rong LiKey Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
Zhi-Zhen HuangDepartment of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
Ying SunJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
Bao-Xue YangDepartment of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China. baoxue@bjmu.edu.cn.
Jin-Peng SunDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China. sunjinpeng@sdu.edu.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Orally bioavailable inhibitors targeting the kidney urea transporter (UT) have the potential to serve as salt-sparing diuretics by employing a urea-selective diuretic mechanism of action distinct from that of diuretics targeting salt transporters. To elucidate the mechanism by which oral inhibitors interact with UTs, we solved the structure of a newly developed inhibitor, E3, with UT-A2 using cryo-electron microscopy. Through structural analysis and binding free energy calculations, we not only revealed the binding mode of E3 to UT-A2 but also clarified the structural basis by which E3 serves as a common competitive inhibitor of human, mouse and rat UT-A/UT-B. E3 exerts its inhibitory effect by competitively binding to the conserved Q-T-T-Q motif in the urea binding pockets of the transport channel. Moreover, we discovered that the BSBP region of UT can serve as a key region for enhancing the inhibitory potency of E3 with different UTs, which provides valuable structural insights for designing and modifying high-affinity UT inhibitors that act as diuretics.

Indexed as

DiureticsUrea TransportersAdministration, OralAnimalsBinding SitesCryoelectron MicroscopyHumansMembrane Transport ProteinsMiceProtein BindingRatsUreaDiureticsMembrane Transport ProteinsUreaUrea Transportersdiureticsinhibitorsstructural characterizationsurea transporter

Identifiers

PMID40523902
PMCPMC12552589

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.