Sandbox Reserved 1782

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (19:45, 10 April 2023) (edit) (undo)
 
(6 intermediate revisions not shown.)
Line 4: Line 4:
== Background ==
== Background ==
-
[[Image:CARTOON.png|400 px|right|thumb|'''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].]]
+
[[Image:Fig_1.png|400 px|right|thumb|'''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 in the body that is responsible for the transportation of bile salts from the blood into epithelial liver cells. This carrier protein is responsible for a conformational change that allows bile salts to cross the cell membrane and enter the inside of liver cells. <Ref> Goutam, K., Ielasi, F.S., Pardon, E. et al. Structural basis of sodium-dependent bile salt uptake into the liver. Nature 606, 1015–1020 (2022). [https://doi.org/10.1038/s41586-022-04723-z DOI: 10.1038/s41586-022-04723-z]. </Ref>. Both sodium ions and bile salts bind to NTCP in the same binding pocket on the molecule (Fig. 1). NTCP also acts as a receptor for Hepatitis B virus and Hepatitis D virus. The bile salts transported by NTCP are located within the gastrointestinal tract of the body and play a very key role in many biological functions. These functions include digesting and absorbing nutrients by helping break down fats and transporting lipid soluble nutrients into the liver. <Ref> Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. [https://doi.org/10.1016/j.cis.2010.12.002 DOI: 10.1016/j.cis.2010.12.002]. </Ref>. The NTCP carrier protein itself can be found within hepatocytes, or the epithelial cells of the liver, but more specifically, within the basolateral membrane of these cells. <Ref name="Asami"> Asami J, Kimura KT, Fujita-Fujiharu Y, Ishida H, Zhang Z, Nomura Y, Liu K, Uemura T, Sato Y, Ono M, Yamamoto M, Noda T, Shigematsu H, Drew D, Iwata S, Shimizu T, Nomura N, Ohto U. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun; 606 (7916):1021-1026. [https://dx.doi.org/10.1038/s41586-022-04845-4 DOI: 10.1038/s41586-022-04845-4]. </Ref>. The uptake of bile salts into the liver also allow for drugs to be both absorbed and excreted, as well as essential nutrients such as Vitamin A,D,E, and K to be absorbed in the small intestine.
+
*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. <Ref name="Goutam"> Goutam, K., Ielasi, F.S., Pardon, E. et al. Structural basis of sodium-dependent bile salt uptake into the liver. Nature 606, 1015–1020 (2022). [https://doi.org/10.1038/s41586-022-04723-z DOI: 10.1038/s41586-022-04723-z]. </Ref> 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. <Ref> Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. [https://doi.org/10.1016/j.cis.2010.12.002 DOI: 10.1016/j.cis.2010.12.002]. </Ref> NTCP is found within the basolateral membrane hepatocytes. <Ref name="Asami"> Asami J, Kimura KT, Fujita-Fujiharu Y, Ishida H, Zhang Z, Nomura Y, Liu K, Uemura T, Sato Y, Ono M, Yamamoto M, Noda T, Shigematsu H, Drew D, Iwata S, Shimizu T, Nomura N, Ohto U. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun; 606 (7916):1021-1026. [https://dx.doi.org/10.1038/s41586-022-04845-4 DOI: 10.1038/s41586-022-04845-4]. </Ref> 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) <scene name='95/952711/Pres1_binding_area_on_ntcp/3'>pre-S1</scene> 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. <ref name="Goutam"/>
 +
 
 +
 
-
=== Structural Overview ===
 
-
Tatiana
 
-
== Function ==
 
-
Olivia
 
=== Binding Pocket ===
=== Binding Pocket ===
-
*The NTCP binding pocket represents a "tunnel" lined with hydrophilic residues within the NTCP structure to allow hydrophilic bile salts and sodium ions to bind. When there are no bile salts bound to NTCP's binding tunnel, it forms a hollow hole in the middle of the structure, from <scene name='95/952710/Tunnel_front/1'>front</scene> to <scene name='95/952710/Tunnel_front/3'>back</scene>. As bile salts bind to this binding pocket, the bile salts very nicely fill the hole within NTCP and fit almost perfectly within the tunnel, to the point where the <scene name='95/952710/Bile_bound_to_tunnel/2'>tunnel</scene> can no longer be seen, as it is completely encompassing the bile salts. This tunnel formed connects the external cytoplasm of the hepatocyte to the inner leaflet of the basolateral membrane. The side of the tunnel where the bile salts bind are lined with hydrophilic residues, whereas the opposite side of the helix is lined with hydrophobic residues, as the transmembrane helices are amphipathic. <Ref name="Liu"> Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). [https://doi.org/10.1038/s41422-022-00680-4 DOI: 10.1038/s41422-022-00680-4]. </Ref>.
+
*<scene name='95/952711/Sodium_residue_zoom_in_nctp/1'>Sodium binds to residues 84-87 and 157-165 within NTCP </scene>. 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. <Ref name="Liu"> Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). [https://doi.org/10.1038/s41422-022-00680-4 DOI: 10.1038/s41422-022-00680-4]. </Ref> The hydrophilic tunnel allows hydrophilic bile salts and sodium ions to be transported across the hydrophobic cell membrane. In the <scene name='95/952710/Tunnel_front/1'>outward facing state</scene> 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 <scene name='95/952710/Bile_bound_to_tunnel/2'>tunnel</scene>.
 +
 
 +
 
 +
[[Image:Patches.png|300 px|left|thumb|'''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 <ref name="Asami"/>. 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 <ref name="Asami"/>.
-
[[Image:Patches.png|400 px|left|thumb|'''Figure 1.''' 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.]]
 
-
*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 <ref name="Asami"/>. 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 <ref name="Asami"/>.
 
== Mechanism ==
== Mechanism ==

Current revision

This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
  • Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

human Sodium Taurocholate Co-transporting Polypeptide (NTCP) structure

Caption for this structure

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 Goutam, K., Ielasi, F.S., Pardon, E. et al. Structural basis of sodium-dependent bile salt uptake into the liver. Nature 606, 1015–1020 (2022). DOI: 10.1038/s41586-022-04723-z.
  2. ↑ Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. DOI: 10.1016/j.cis.2010.12.002.
  3. ↑ 3.0 3.1 3.2 Asami J, Kimura KT, Fujita-Fujiharu Y, Ishida H, Zhang Z, Nomura Y, Liu K, Uemura T, Sato Y, Ono M, Yamamoto M, Noda T, Shigematsu H, Drew D, Iwata S, Shimizu T, Nomura N, Ohto U. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun; 606 (7916):1021-1026. DOI: 10.1038/s41586-022-04845-4.
  4. ↑ Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). DOI: 10.1038/s41422-022-00680-4.

Student Contributors

  • Kenna King
  • Tatiana Pereda
  • Olivia Simcox
Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1782"
Personal tools