Background

Figure 1. NTCP structure with both Na+ ions and bile salts bound with the NTCP molecule shown in light blue, the two Na+ ions shown in purple spheres, and the bile salts shown in sticks as dark blue. [PDB file 7ZYI].

• Sodium taurocholate co-transporting polypeptide (NTCP) is a sodium-dependent transporter that is responsible for the transportation of bile salts from the blood into epithelial liver cells. ^[1] NTCP is a secondary active transport molecule that couples the thermodynamically favorable movement of Na+ ions with the unfavorable transport of bile salts into the cell (Fig. 1).

• The bile salts transported by NTCP in the gastrointestinal tract are involved in digestion, nutrient absorption, fat breakdown, and lipid soluble nutrient transport. ^[2] NTCP is found within the basolateral membrane hepatocytes. ^[3] The uptake of bile salts into the liver also allow for drugs and fat soluble vitamins to be both absorbed and excreted in the small intestine. NTCP also acts as a receptor for Hepatitis B virus (HBV) and Hepatitis D virus (HDV) which infect human livers through endocytosis when bound. The myristoylated (myr) domain of HBV, specifically residues 8-17, is critical for its binding to NTCP which halts the uptake of bile salts, indicating that HBV/HDV bind to NTCP at the same site as bile salts. ^[1]

Binding Pocket

• . The binding pocket forms a tunnel structure within NTCP at the interface of two domains that connects the external cytoplasm of the hepatocyte to the basolateral membrane. The face of the tunnel where the bile salts bind is lined with hydrophilic residues, whereas the opposite face of the transmembrane helices is hydrophobic, making the tunnel amphipathic. ^[4] The hydrophilic tunnel allows hydrophilic bile salts and sodium ions to be transported across the hydrophobic cell membrane. In the with no bile salt bound to the tunnel, it forms a hollow hole in the middle of the structure. When bile salts bind within, these bile salts completely occlude the .

Figure 2. Surface representation of the NTCP molecule with both patches shown. Patch 1 can be seen on the left side of the molecule, whereas patch 2 is located on the right side within the binding tunnel. [PDB file 7ZYI].

HBV/HDV Binding Pocket

The binding pocket of NTCP contains two patches on its exterior. These two patches are used for assisting in the binding of bile salts into the binding tunnel. These external patches are extremely important for aiding in the transport of bile salts from the exterior of NTCP to the interior binding tunnel ^[3]. Patch 1 is made up of residues 84-87 of NTCP and Patch 2 consists of residues 157-165. Patch 1 is located on the poles of NTCP, namely the top of the structure, within the TM2-TM3 transmembrane loop, whereas patch 2 is located towards the middle of the NTCP molecule within transmembrane 5 (TM5). These two patches are also predominantly responsible for binding the preS1 binding region of the HBV/HDV virus. Patch 2 also forms a part of the binding tunnel previously mentioned ^[3].

Mechanism

Olivia

Significance

Olivia

HBV/ HDV

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