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

Shen-Ming Huang, Zhi-Zhen Huang, Lei Liu, Meng-Yao Xiong, Chao Zhang, Bo-Yang Cai, Ming-Wei Wang, Kui Cai, Ying-Li Jia, Jia-Le Wang, Ming-Hui Zhang, Yi-He Xie, Min Li, Hang Zhang, Cheng-Hao Weng, Xin Wen, Zhi Li, Ying Sun, Fan Yi, Zhao Yang, Peng Xiao, Fan Yang, Xiao Yu, Lu Tie (), Bao-Xue Yang () and Jin-Peng Sun ()
Additional contact information
Shen-Ming Huang: Peking University
Zhi-Zhen Huang: Peking University
Lei Liu: Shandong University
Meng-Yao Xiong: Peking University
Chao Zhang: Shandong University
Bo-Yang Cai: Peking University
Ming-Wei Wang: Shandong University
Kui Cai: Peking University
Ying-Li Jia: Peking University
Jia-Le Wang: Peking University
Ming-Hui Zhang: Qilu Hospital of Shandong University
Yi-He Xie: Peking University
Min Li: Peking University
Hang Zhang: Peking University
Cheng-Hao Weng: Peking University
Xin Wen: Shandong University
Zhi Li: Xuzhou Medical University
Ying Sun: Xuzhou Medical University
Fan Yi: Shandong University
Zhao Yang: Shandong University
Peng Xiao: Shandong University
Fan Yang: Shandong University
Xiao Yu: Shandong University
Lu Tie: Peking University
Bao-Xue Yang: Peking University
Jin-Peng Sun: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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 QPb-T5b-T5a-QPa 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54305-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54305-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54305-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().