8TZ8

Cryo-EM structure of bovine concentrative nucleoside transporter 3 in complex with Molnupiravir, condition 1, INT1-INT1-INT3 conformation

Summary for 8TZ8

• Entry DOI: 10.2210/pdb8tz8/pdb
• EMDB information: 41737
• Descriptor: Sodium/nucleoside cotransporter, N-hydroxy-5'-O-(2-methylpropanoyl)cytidine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (3 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: 240638.39

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

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: 38418906
DOI: 10.1038/s41589-024-01559-8

Experimental method

ELECTRON MICROSCOPY (3.19 Å)