Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters PMID: 39587082

Target-related Cytokines

2026-09-23

Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters

Nat Commun. 2024 Nov 26;15(1):10226. doi: 10.1038/s41467-024-54305-y.

Shen-Ming Huang ^# ¹ ² , Zhi-Zhen Huang ^# ³ , Lei Liu ^# ² ⁴ , Meng-Yao Xiong ^# ¹ ³ , Chao Zhang ^# ⁵ , Bo-Yang Cai ^# ¹ , Ming-Wei Wang ^# ² , Kui Cai ¹ , Ying-Li Jia ¹ , Jia-Le Wang ¹ , Ming-Hui Zhang ⁶ , Yi-He Xie ¹ , Min Li ³ , Hang Zhang ³ , Cheng-Hao Weng ¹ , Xin Wen ² , Zhi Li ⁷ , Ying Sun ⁷ , Fan Yi ⁸ , Zhao Yang ⁵ , Peng Xiao ⁵ , Fan Yang ² ⁹ , Xiao Yu ⁹ , Lu Tie ¹⁰ , Bao-Xue Yang ¹¹ , Jin-Peng Sun ¹² ¹³ ¹⁴

Affiliations

1. 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, China.
2. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
3. Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
4. The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
5. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
6. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
7. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
8. The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
9. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
10. Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
11. Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
12. 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, China. [email protected].
13. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
14. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
# Contributed equally.

Abstract

Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the Q^Pb-T^5b-T^5a-Q^Pa motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics.