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.
Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Nat Commun. 2024 Nov 26;15(1):10226. doi: 10.1038/s41467-024-54305-y.
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-T-T-Q 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.
尿素通过尿素转运体（UT）的跨膜转运是生命活动的基本生理行为。在这里，我们展示了四个 UT 成员在静止状态、尿素转运状态或与合成竞争性、非竞争性或非竞争性抑制剂结合的非活性状态下的 11 个冷冻电镜结构。我们的结果表明，尿素通过保守的尿素识别基序（URM）结合，并且通过不同 UT 成员之间的 Q-T-T-Q 基序的氢键转移进行尿素转运。此外，竞争性抑制剂 25a 和 ATB3、非竞争性抑制剂 CF11 和竞争性抑制剂 HQA2 的不同结合模式分别通过 L-P 口袋、UCBP 区域和 SCG 口袋为阻断尿素转运提供了不同的机制，并实现了选择性。综上所述，我们的研究不仅允许通过 UT 进行尿素转运的结构理解，而且还提供了竞争性、非竞争性和非竞争性抑制剂抑制 hUT-A2 的结构全景，这可能有助于开发选择性人 UT-A 抑制剂作为一类新型的保盐利尿剂。
