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Background

Structural Overview

There are two significant areas in the NTCP structure that facilitate ligand binding, which are referred to as "patches." Residues 84-87 of NTCP are patch 1, which are located on the TM2-TM3 loop in the core domain. This is also considered the extracellular region of NTCP “tunnel." Residues 157-165 NTCP are associated with patch 2. They are located on N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in th extracellular region. These residues' importance was determined through mutations of these residues and examined through pull-down assays (Asami, et. al, 2022).

Binding Pocket

Confirmation Change

Mechanism

Figure 1. Bile Salt Uptake Mechanism.

The NTCP protein goes through a conformational change when assisting in the uptake of bile salt into the cell. This is accomplished through the opening of a wide transmembrane pore, creating a transport pathway for bile salts. The mechanism includes two sodium metal ions that allow for residue stabilization when going through the conformational change. Binding of the preS1 region of the HBV/HDV virus blocks any subsequent bile salt uptake. Thus, preS1 binding blocks the conformational change and entry of any salts into the cell. Residues 8-17 of preS1 are critical for NTCP:pres1 binding. Patch 1 and Patch 2 (external) residues interact with residues 8-17 of preS1 to facilitate binding.

Function

Significance

NTCP is a key player in the absorption and digestion of fats and fat-soluble vitamins in the body, as well as the synthesis of bile within the liver. The uptake of bile salts, transcriptional and post-transcriptional, are signaling molecules for the liver and intestine. Bile salt, the transporting molecule of NTCP, aids in the absorption of lipophilic nutrients and vitamins in the small intestine. Additionally, bile salt plays a role in the endocrine system, excretion of toxins, and cholesterol maintenance. ADD GOUTAM REFERENCE HERE. Thus, the significance of NTCP lies with the importance of bile salts; NTCP is necessary in maintaining bile salt levels and thus necessary in maintaining the aforementioned biological processes.

Bile Salt Uptake

Figure 2. Bile Salt Structure.

Cirrhosis, commonly known as the last stage of liver disease, is due to a deficiency in the bile acid supply in the liver. Bile acid pools, as defined by Vlahcevic, are the negatively-charged precursors to bile and often are conjugated to positively-charged bile salts. This is attributed either a decrease in the production of bile salts or a large increase in the excretion of this molecule out of the cell. https://www.gastrojournal.org/article/S0016-5085(71)80053-7/pdf This disease is transferred through bodily fluids between organisms. Liver Disease causes symptoms such as jaundice, abdominal pain and swelling, and swelling of the legs and feet. Liver disease can lead to liver cancer and other life-threatening diseases, making bile salt uptake essential to liver function.

HBV/HDV