8TZ5
Cryo-EM structure of bovine concentrative nucleoside transporter 3 in complex with N-hydroxycytidine
Summary for 8TZ5
Entry DOI | 10.2210/pdb8tz5/pdb |
EMDB information | 41734 |
Descriptor | Sodium/nucleoside cotransporter, N-hydroxycytidine, SODIUM ION, ... (4 entities in total) |
Functional Keywords | membrane protein, transporter, nucleoside, transport protein |
Biological source | Bos taurus (cattle) |
Total number of polymer chains | 3 |
Total formula weight | 248097.85 |
Authors | Wright, N.J.,Lee, S.-Y. (deposition date: 2023-08-26, release date: 2024-03-13, Last modification date: 2024-09-18) |
Primary citation | Wright, N.J.,Zhang, F.,Suo, Y.,Kong, L.,Yin, Y.,Fedor, J.G.,Sharma, K.,Borgnia, M.J.,Im, W.,Lee, S.Y. Antiviral drug recognition and elevator-type transport motions of CNT3. Nat.Chem.Biol., 20:1144-1153, 2024 Cited by PubMed Abstract: Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human concentrative nucleoside transporter 3 (CNT3) interacts with antiviral drugs used in the treatment of coronavirus infections. We report high-resolution single-particle cryo-electron microscopy structures of bovine CNT3 complexed with antiviral nucleosides N-hydroxycytidine, PSI-6206, GS-441524 and ribavirin, all in inward-facing states. Notably, we found that the orally bioavailable antiviral molnupiravir arrests CNT3 in four distinct conformations, allowing us to capture cryo-electron microscopy structures of drug-loaded outward-facing and drug-loaded intermediate states. Our studies uncover the conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug, yield new insights into the role of interactions between the transport and the scaffold domains in elevator-like domain movements during drug translocation, and provide insights into the design of nucleoside analog antiviral prodrugs with improved oral bioavailability. PubMed: 38418906DOI: 10.1038/s41589-024-01559-8 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (2.74 Å) |
Structure validation
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