Abstract
Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug interactions. In the kidneys, OATs facilitate the elimination of metabolic waste products and xenobiotics. However, their transport activities can lead to the accumulation of certain toxic compounds within cells, causing kidney damage. Moreover, OATs are important drug targets, because their inhibition modulates the elimination or retention of substrates linked to diseases. Despite extensive research on OATs, the molecular basis of their substrate and inhibitor binding remains poorly understood. Here we report the cryo-EM structures of rat OAT1 (also known as SLC22A6) and its complexes with para-aminohippuric acid and probenecid at 2.1, 2.8 and 2.9 Å resolution, respectively. Our findings reveal a highly conserved substrate binding mechanism for SLC22 transporters, wherein four aromatic residues form a cage to accommodate the polyspecific binding of diverse compounds.
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Data availability
The cryo-EM density maps of apo-rOAT1, the rOAT1–PAH complex and the rOAT1–probenecid complex have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-40352 (refined by CryoSPARC), EMD-40354 and EMD-40355, respectively. The map of apo-rOAT1 refined by RELION4 is available with accession code EMD-40948. The atomic coordinates of the structures of apo-rOAT1, the rOAT1–PAH complex and the rOAT1–probenecid complex have been deposited in the Protein Data Bank (PDB) under accession codes 8SDU, 8SDY and 8SDZ, respectively. The modified version of RELION4 used in this work is available at GitHub https://github.com/jiangjiansen/relion_composite_masks. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Intramural Research Program at the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). This work utilized the NIH Multi-Institute Cryo-EM Facility (MICEF), the computational resources of the NIH High Performing Computation (HPC) Biowulf cluster (http://hpc.nih.gov) and the instruments maintained by the NHLBI Biochemistry Core. We thank H. Wang, Y. Cui and H. He for technical support on the electron microscopes and R. Saracuza for technical support on installation and maintenance of the in-house GPU computers.
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J.J. conceived the project. T.D., T.L., S.S. and Y.H. conducted cell culture and protein expression. T.D. and T.L. performed protein purification and cryo-EM sample preparation. T.D., T.L. and J.J. performed cryo-EM data collection and processing. T.D. and J.J. built the atomic models. J.J. and T.D. wrote the manuscript with input from all of the authors.
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Extended data
Extended Data Fig. 1 Protein purification of rOAT1.
a, Size exclusion chromatography (SEC) elution profile of rOAT1. b, SDS-PAGE image of purified rOAT1. The purification of rOAT1 was repeated more than three times with similar results.
Extended Data Fig. 2 Cryo-EM data of rOAT1.
a, A representative motion-corrected cryo-EM micrograph of rOAT1. A total of over 20,000 micrographs with a quality similar to this one were collected for this work. b, Representative 2D class averages of rOAT1 particles. The side length of each image box is 212 Å.
Extended Data Fig. 3 Cryo-EM data processing workflow for apo-rOAT1.
A set of composite masks used in 3D classification and 3D auto-refinement is shown at the top.
Extended Data Fig. 4 Cryo-EM data processing workflow for the rOAT1-PAH complex.
The 3D reconstruction of apo-rOAT1 was used as the initial model. Some top-view particles were randomly removed before the final 3D auto-refinement to improve the particle orientation distribution.
Extended Data Fig. 5 Cryo-EM data processing workflow for the rOAT1-probenecid complex.
The 3D reconstruction of apo-rOAT1 was used as the initial model.
Extended Data Fig. 6 Resolution estimation of cryo-EM 3D reconstructions of apo-rOAT1, the rOAT1-PAH complex, and the rOAT1-probenecid complex.
a-c, FSC curves (left), particle orientation plots (middle), and local resolution maps (right) of the 3D reconstructions of apo-rOAT1 (a), the rOAT1-PATH complex (b), and the rOAT1-probenecid complex (c). d, FSC curves of non-uniform 3D refinement of apo-rOAT1 using cryoSPARC.
Extended Data Fig. 7 High-resolution details in the cryo-EM density map of apo-rOAT1.
a-c, The cryo-EM densities (grey surfaces) of the transmembrane helices (a), the ECD (b), and the ICD (c) superimposed with the atomic model. d,e, Close-up views of the disulfide bonds in the ECD, showing the cryo-EM density map (grey surfaces) superimposed with the atomic model.
Extended Data Fig. 8 Comparison of the cryo-EM density maps of apo-rOAT1, the rOAT1-PAH complex, and the rOAT1-probenecid complex near the region of the substrate binding site.
a, apo-rOAT1. b, The rOAT1-PAH complex. c, The rOAT1-probenecid complex. The cryo-EM density maps are shown as grey surfaces. The residues of rOAT1 are colored in medium purple (NTD) or cyan (CTD). Water molecules are depicted by red spheres.
Extended Data Fig. 9 Cryo-EM density map of the PAH binding site in the rOAT1-PAH complex.
Three possible models of PAH (white stick models) are superimposed with the cryo-EM density map (grey surfaces) separately. The residues of rOAT1 are colored in medium purple (NTD) or cyan (CTD).
Extended Data Fig. 10 Cryo-EM density map of the probenecid binding site in the rOAT1-probenecid complex.
a, The cryo-EM density map (grey surfaces) of the rOAT1-probenecid complex superimposed with the atomic model. Probenecid is shown as a grey stick model. b, The same view of the cryo-EM density map of apo-rOAT1.
Supplementary information
Supplementary Information
Supplementary Fig. 1.
Supplementary Video 1
Overall structure of apo-rOAT1. The sharpened cryo-EM map of apo-rOAT1 superimposed with the atomic model is first shown, followed by the atomic model with the transmembrane helices rainbow colored.
Supplementary Video 2
Water molecules in the structure of apo-rOAT1. The cryo-EM densities of bound/ordered water molecules are shown as gray surfaces. The hydrogen bonds involving water molecules are depicted by orange dashed lines.
Supplementary Video 3
The binding of PAH in rOAT1. The cryo-EM density map of the rOAT1–PAH complex (gray surface) is superimposed with the atomic model. Three possible poses of PAH (white stick model) in the binding site are shown sequentially.
Supplementary Video 4
The binding of probenecid in rOAT1. The cryo-EM density map of the rOAT1–probenecid complex (gray surface) is superimposed with the atomic model. Probenecid is shown as a gray stick model in the center.
Supplementary Video 5
A putative conformational conversion between the inward-facing and outward-facing states of rOAT1. The animation shows the morph between the inward-facing structure and the outward-facing model of rOAT1. The NTD and CTD rotate as rigid bodies without considering conformational changes within each of the two domains. The side chains of the charged residues (Asp, Glu, Lys, and Arg) are shown as ball-and-stick models.
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Source Data Extended Data Fig. 1b
Unprocessed scan of gel.
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Dou, T., Lian, T., Shu, S. et al. The substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM. Nat Struct Mol Biol 30, 1794–1805 (2023). https://doi.org/10.1038/s41594-023-01123-3
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DOI: https://doi.org/10.1038/s41594-023-01123-3
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