Cryo-EM structures of human organic anion transporting polypeptide OATP1B1.

Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.

Deciphering urban traffic impacts on air quality by deep learning and emission inventory.

Air pollution is a major obstacle to future sustainability, and traffic pollution has become a large drag on the sustainable developments of future metropolises. Here, combined with the large volume of real-time monitoring data, we propose a deep learning model, iDeepAir, to predict surface-level PM2.5 concentration in Shanghai megacity and link with MEIC emission inventory creatively to decipher urban traffic impacts on air quality. Our model exhibits high-fidelity in reproducing pollutant concentrations and reduces the MAE from 25.355 µg/m3 to 12.283 µg/m3 compared with other models. And identifies the ranking of major factors, local meteorological conditions have become a nonnegligible factor. Layer-wise relevance propagation (LRP) is used here to enhance the interpretability of the model and we visualize and analyze the reasons for the different correlation between traffic density and PM2.5 concentration in various regions of Shanghai. Meanwhile, As the strict and effective industrial emission reduction measurements implementing in China, the contribution of urban traffic to PM2.5 formation calculated by combining MEIC emission inventory and LRP is gradually increasing from 18.03% in 2011 to 24.37% in 2017 in Shanghai, and the impact of traffic emissions would be ever-prominent in 2030 according to our prediction. We also infer that the promotion of vehicular electrification would achieve further alleviation of PM2.5 about 8.45% by 2030 gradually. These insights are of great significance to provide the decision-making basis for accurate and high-efficient traffic management and urban pollution control, and eventually benefit people's lives and high-quality sustainable developments of cities.

Cryo-EM structure of the human sodium-chloride cotransporter NCC.

The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 Å for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC.