Academic Journal
Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters
| Title: | Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters |
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| Authors: | 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, Jin-Peng Sun |
| Source: | Nature Communications, Vol 15, Iss 1, Pp 1-17 (2024) |
| Publisher Information: | Nature Portfolio, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Science |
| Subject Terms: | Science |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2041-1723 09414444 |
| Relation: | https://doaj.org/toc/2041-1723 |
| DOI: | 10.1038/s41467-024-54305-y |
| Access URL: | https://doaj.org/article/45cc969e094144449570478a54b118c0 |
| Accession Number: | edsdoj.45cc969e094144449570478a54b118c0 |
| Database: | Directory of Open Access Journals |
| ISSN: | 20411723 09414444 |
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| DOI: | 10.1038/s41467-024-54305-y |
| Published in: | Nature Communications |
| Language: | English |