Hepatitis: 3D structure determination of the ‘gateway’ to the liver

Although an important gateway to the liver, NTCP had not been well described until now. Na + -taurocholate co-transporting polypeptide (NTCP) is a protein located exclusively in the membranes of liver cells that enables the recovery of bile acid molecules. It is also the cellular receptor for human hepatitis B and D viruses (HBV / HDV). A better understanding of NTCP may enable the development of treatments specifically designed for the liver and to combat HBV and HDV infection.

NTCP is a difficult protein to study. It weighs only 38 kilodaltons (kDa)1, while cryo-electron microscopy, the technique used to study this type of molecule, only works for molecules weighing more than 50 kDA. The challenge was therefore to “enlarge” and stabilize it.

To do this, teams from French and Belgian laboratories2 developed and tested a collection of antibody fragments directed against NTCP. The 3D structures of the resulting complexes were determined by cryoelectron microscopy, and various antibody fragments were stabilized, revealing several forms of NTCP.

The research team was able to describe two essential NTCP conformations: one in which the protein opens a large membrane pore for bile salts, to which HBV and HDV can bind, and a second, “closed” conformation, which prevents virus recognition.

The first, “open” conformation is very surprising, since no other known molecular carrier forms such a “wide open” pore. In turn, the second conformation can help find antiviral molecules that prevent HBV and HDV infection. The research group intends to continue its work to fully clarify how NTCP works.

Footnotes

1- A dalton is one twelfth of the mass of a carbon-12 atom (the mass of a hydrogen atom, roughly).

2- The study was conducted by teams at the MPF Laboratory (Microbiology fundamental and pathogenicity) (CNRS / University of Bordeaux), the unit for membrane protein mechanisms at the Institut Pasteur and the VIB-VUB Center for Structural Biology. This study was supported by the ANRS Emerging Infectious Diseases Program, among others.

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