Sandbox Reserved 1769: Difference between revisions

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Structures were determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryogenic electron microscopy (Cryo-EM)] of NTCP in complex with antibodies or nanobodies, revealing two key conformations in NTCP's transport mechanism. There are nine transmembrane [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] traversing the plasma membrane, with the [https://en.wikipedia.org/wiki/N-terminus N-terminus] located on the extracellular side of the plasma membrane and the [https://en.wikipedia.org/wiki/C-terminus C-terminus] located on the intracellular side. The panel domain is formed by transmembrane helices TM1, TM5, and TM6. The core domain is formed by the packing of a helix bundle consisting of TM2, TM3, and TM4 with another helix bundle consisting of TM7, TM8, and TM9. The two helix bundles are related by pseudo two-fold symmetry. Transmembrane helices are connected by short loops as well as extracellular and intracellular alpha helices that lie nearly parallel to the membrane.

~~=== Proline/Glycine Hinge ===~~

=== Domains ===

NTCP contains two characteristic domains, the core and panel domains. Movement of these two domains ~~characterizes the two known conformational states implied in the mechanism~~ of bile ~~salt uptake~~.

NTCP contains two characteristic domains: the core and panel domains. Movement of these two domains allows recognition and transport of bile salts into hepatocytes.

*Panel Domain: 1-44, 155-208

*Core domain: 45-154, 209-309

=== Proline/Glycine Hinge ===

Glycine and proline residues in the connecting loops and extra- and intracellular helices act as hinges in the mechanism of bile salt uptake. The flexibility allows separation of the core and panel domains, creating a pore open to the extracellular space and exposing critical Na+ binding sites. Once substrate binds the open-pore state, this hinge allows transition to close this pore relative to the extracellular side and open to the cytoplasmic side, thus allowing release of substrate into the cell.

=== Sodium Binding Sites ===

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=== Mechanism of Bile Salt Uptake ===

Bile salts recognize and bind to the open-pore state.

<scene name='95/952697/Ntcp_open-pore_state_surface/1'>NTCP Open-Pore State</scene>

<scene name='95/952697/Ntcp_inward_facing_state/1'>Inward Facing State</scene>

=== Mechanism of HBV/HDV Infection ===

~~HBV/HDV infection is reliant on multiple properties that must be present on both the virus itself and the NTCP protein. First, the~~ HBV/HDV capsid must be myristoylated (INSERT BLUE LINK) in order for proper recognition by NTCP. Residues 2-48 are the most significant residues of HBV/HDV that are highly conserved amongst these viruses that are vital for infection. Specifically, residues 8-17 on HBV/HDV have been identified as the most important. These residues are NPLGFFPDHQ. There are two proposed mechanisms as to how exactly HBV/HDV bind to NTCP and enter the cell. In both mechanisms, there is an initial translocation of the myristoylated preS1 HBV/HDV virus to interact with the host cell (hepatocyte). The first mechanism involves the myristoyl group of preS1 binding to the host cell membrane, not NTCP, and residues P8-H17 interacting with NTCP residues 157-165. The second mechanism involves the myristoyl group of preS1 binding directly into the open-pore of NTCP interacting with residues 157-165. In both proposed mechanisms, the interactions with the extracellular residues 84-87 of NTCP is unknown.

The HBV/HDV capsid must be myristoylated (INSERT BLUE LINK) in order for proper recognition by NTCP. Residues 2-48 are the most significant residues of HBV/HDV that are highly conserved amongst these viruses that are vital for infection. Specifically, residues 8-17 on HBV/HDV have been identified as the most important. These residues are NPLGFFPDHQ. There are two proposed mechanisms as to how exactly HBV/HDV bind to NTCP and enter the cell. In both mechanisms, there is an initial translocation of the myristoylated preS1 HBV/HDV virus to interact with the host cell (hepatocyte). The first mechanism involves the myristoyl group of preS1 binding to the host cell membrane, not NTCP, and residues P8-H17 interacting with NTCP residues 157-165. The second mechanism involves the myristoyl group of preS1 binding directly into the open-pore of NTCP interacting with residues 157-165. In both proposed mechanisms, the interactions with the extracellular residues 84-87 of NTCP is unknown.

Sandbox Reserved 1769: Difference between revisions

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@@ Line 14: / Line 14: @@
 Structures were determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryogenic electron microscopy (Cryo-EM)] of NTCP in complex with antibodies or nanobodies, revealing two key conformations in NTCP's transport mechanism. There are nine transmembrane [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] traversing the plasma membrane, with the [https://en.wikipedia.org/wiki/N-terminus N-terminus] located on the extracellular side of the plasma membrane and the [https://en.wikipedia.org/wiki/C-terminus C-terminus] located on the intracellular side. The panel domain is formed by transmembrane helices TM1, TM5, and TM6. The core domain is formed by the packing of a helix bundle consisting of TM2, TM3, and TM4 with another helix bundle consisting of TM7, TM8, and TM9. The two helix bundles are related by pseudo two-fold symmetry. Transmembrane helices are connected by short loops as well as extracellular and intracellular alpha helices that lie nearly parallel to the membrane.
-=== Proline/Glycine Hinge ===
 === Domains ===
-NTCP contains two characteristic domains, the core and panel domains. Movement of these two domains characterizes the two known conformational states implied in the mechanism of bile salt uptake.
+NTCP contains two characteristic domains: the core and panel domains. Movement of these two domains allows recognition and transport of bile salts into hepatocytes.
 *<b><font color="orange">Panel Domain</font></b>: 1-44, 155-208
 *<b><font color="#0040e0">Core domain</font></b>: 45-154, 209-309
+=== Proline/Glycine Hinge ===
+Glycine and proline residues in the connecting loops and extra- and intracellular helices act as hinges in the mechanism of bile salt uptake. The flexibility allows separation of the core and panel domains, creating a pore open to the extracellular space and exposing critical Na+ binding sites. Once substrate binds the open-pore state, this hinge allows transition to close this pore relative to the extracellular side and open to the cytoplasmic side, thus allowing release of substrate into the cell.
 === Sodium Binding Sites ===
@@ Line 29: / Line 32: @@
 === Mechanism of Bile Salt Uptake ===
+Bile salts recognize and bind to the open-pore state.
 <scene name='95/952697/Ntcp_open-pore_state_surface/1'>NTCP Open-Pore State</scene>
 <scene name='95/952697/Ntcp_inward_facing_state/1'>Inward Facing State</scene>
 === Mechanism of HBV/HDV Infection ===
-HBV/HDV infection is reliant on multiple properties that must be present on both the virus itself and the NTCP protein. First, the HBV/HDV capsid must be myristoylated (INSERT BLUE LINK) in order for proper recognition by NTCP. Residues 2-48 are the most significant residues of HBV/HDV that are highly conserved amongst these viruses that are vital for infection. Specifically, residues 8-17 on HBV/HDV have been identified as the most important. These residues are NPLGFFPDHQ. There are two proposed mechanisms as to how exactly HBV/HDV bind to NTCP and enter the cell. In both mechanisms, there is an initial translocation of the myristoylated preS1 HBV/HDV virus to interact with the host cell (hepatocyte). The first mechanism involves the myristoyl group of preS1 binding to the host cell membrane, not NTCP, and residues P8-H17 interacting with NTCP residues 157-165. The second mechanism involves the myristoyl group of preS1 binding directly into the open-pore of NTCP interacting with residues 157-165. In both proposed mechanisms, the interactions with the extracellular residues 84-87 of NTCP is unknown.
+The HBV/HDV capsid must be myristoylated (INSERT BLUE LINK) in order for proper recognition by NTCP. Residues 2-48 are the most significant residues of HBV/HDV that are highly conserved amongst these viruses that are vital for infection. Specifically, residues 8-17 on HBV/HDV have been identified as the most important. These residues are NPLGFFPDHQ. There are two proposed mechanisms as to how exactly HBV/HDV bind to NTCP and enter the cell. In both mechanisms, there is an initial translocation of the myristoylated preS1 HBV/HDV virus to interact with the host cell (hepatocyte). The first mechanism involves the myristoyl group of preS1 binding to the host cell membrane, not NTCP, and residues P8-H17 interacting with NTCP residues 157-165. The second mechanism involves the myristoyl group of preS1 binding directly into the open-pore of NTCP interacting with residues 157-165. In both proposed mechanisms, the interactions with the extracellular residues 84-87 of NTCP is unknown.