Human Na+ taurocholate (TCA) co-transporting protein (hNTCP), is key bile salt transporter for the maintenance of enterohepatic circulation and is also responsible to recognize the hepatitis B and D viruses (HBV/HDV). Cryo-electron microscopy (cryo-EM) studies revealed the open-pore and inward-facing states of NTCP stabilized by HBV antibodies. However, little is known about the inherent mechanism for Na+-driven bile acid transport in hNTCP. Here, we use classical molecular dynamics (MD) simulations and metadynamics (MetaD) to elucidate the mechanisms of how hNTCP transport TCA coupled with Na+-binding. We elucidate the unsolved TCA binding mode cooperating with the open-pore state of hNTCP, which is matched very well with the partial cryo-EM density. We capture the other critical conformations in the transport cycle: dynamic-apo, outward-bound, and inward-bound states. We find thermodynamic evidence to support: Na+-bound state changes energetically drive TCA transport; TCA translocation-coupled hNTCP conformational transition to access the inward-facing state is spontaneous. We construct the full substrate transport cycle of hNTCP and provide fresh insights into the mechanistic details of the hNTCP transport substrate gated by the Na+. Those mechanisms are useful for developing therapies by modulating bile acid transport in hNTCP.

Molecular mechanisms of Na+-driven bile acid transport in human NTCP

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