May 20, 2024

3D Structure of the “Gateway” to the Liver Could Enable Treatments To Fight Hepatitis

A kilodalton is an atomic mass unit equivalent to 1,000 daltons. One dalton is one-twelfth the mass of a carbon-12 atom (the mass of a hydrogen atom, approximately).
The study was carried out by groups at the MPF Laboratory (Microbiologie fondamentale et pathogénicité) (CNRS/University of Bordeaux), the Membrane Protein Mechanisms Unit at the Institut Pasteur, and the VIB-VUB Center for Structural Biology. This study was supported by the ANRS Emerging Infectious Diseases Program, to name a few.

Illustration of the two 3D conformations embraced by NTCPs. Left: open conformation to which HBV and HDV can bind. Right: closed conformation that avoids recognition by the viruses. Credit: © Kapil Goutam/Nicolas Reyes/CNRS
It is an important entrance to the liver, NTCP had actually not been well explained prior to now. Na+- taurocholate co-transporting polypeptide (NTCP) is a protein located solely in the membrane of liver cells that allows recycling of bile acid molecules. It is also the cellular receptor of human liver disease B and D viruses (HBV/HDV). A much better understanding of NTCP could make it possible for the development of treatments particularly developed for the liver, and to eliminate HBV and HDV infection.
NTCP is a hard protein to study. It weighs just 38 kilodaltons (kDa) [1], whereas cryo-electron microscopy, the technology used to study this type of molecule, just works for molecules weighing more than 50 kDA. The challenge was therefore to “expand” and support it.
To do this, groups from French and Belgian laboratories [2] established and tested a collection of antibody pieces targeting NTCP. The 3D structures of the resulting complexes were figured out utilizing cryo-electron microscopy, and different antibody fragments supported and exposed numerous kinds of NTCP.

Illustration of the 2 3D conformations adopted by NTCPs. Left: open conformation to which HBV and HDV can bind.: closed conformation that avoids acknowledgment by the infections. The very first, open conformation is very surprising, as no other known molecular transporter kinds such a large open pore. In turn, the second conformation could assist in discovering antiviral particles that avoid HBV and HDV infection.

The group of scientists was able to explain 2 necessary NTCP conformations: one in which the protein opens a large membrane pore to bile salts, to which HBV and HDV can bind, and a second, closed conformation, that prevents recognition by the infections.
The first, open conformation is really unexpected, as no other recognized molecular transporter kinds such a wide open pore. In turn, the second conformation could help in finding antiviral molecules that prevent HBV and HDV infection. The group of researchers intends to continue its work to fully clarify the functioning of NTCP.
Reference: “Structural basis of sodium-dependent bile salt uptake into the liver” 11 May 2022, Nature.DOI: 10.1038/ s41586-022-04723-z.