Sandbox Reserved 1783: Difference between revisions

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NTCP has 9 transmembrane alpha helices (TM) that form the protein, with an extracellular N-terminus and intracellular C-terminus. NTCP has two domains within the protein, <scene name='95/952711/Panel_domain/1'>a panel domain</scene>, made up of TM1, TM5, and TM6, and <scene name='95/952711/Core_domain/3'>a core domain</scene>, made up of TM2-4 and TM7-9. An interesting feature of NTCP is the cross of TM3 and TM8 that form an <scene name='95/952711/X_motif/1'>X motif</scene> within the protein that is used in the conformational change of NTCP. The two domains are essential to the conformation change of NTCP to bind bile salts <Ref name="Xiangbing"> Xiangbing Qi, Wenhui Li. (2022). Unlocking the secrets to human NTCP structure. The Innovation, Vol. 3, Issue 5. 100294, ISSN 2666-6758, [https://doi.org/10.1016/j.xinn.2022.100294 DOI: 10.1016/j.xinn.2022.100294]. </Ref>.

There are two significant patches in the NTCP structure that facilitate ligand binding. Residues 84-87 of NTCP are Patch 1, which are located on the TM2-TM3 loop in the core domain. This patch is also considered the extracellular region of the binding tunnel within NTCP. Residues 157-165 of NTCP are associated with <scene name='95/952711/Binding_site_2_with_surface/1'>Patch 2</scene>. They are located on the N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in the extracellular region of the binding tunnel. These residues' importance was determined through mutations of these residues and examined through pull-down assays <ref name="Asami"/>. The pre-S1 domain of HBV/HDV binds to the patches on NTCP in order to transport the virus from the exterior of NTCP to the interior binding tunnel to infect human liver cells.

There are two significant patches in the NTCP structure that facilitate ligand binding. Residues 84-87 of NTCP are Patch 1, which are located on the TM2-TM3 loop in the core domain. This patch is also considered the extracellular region of the binding tunnel within NTCP. Residues 157-165 of NTCP are associated with <scene name='95/952711/Binding_site_2_with_surface/1'>Patch 2</scene>. They are located on the N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in the extracellular region of the binding tunnel. These residues' importance was determined through mutations of these residues and examined through pull-down assays <ref name="Asami"/>. The pre-S1 domain of HBV/HDV binds to the patches on NTCP in order to transport the virus from the exterior of NTCP to the interior binding tunnel to infect human liver cells. (Goutam)

[[Image:Figuredomain.png|450 px|right|thumb|'''Figure 3.''' Cartoon of NTCP topology.]]

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=== Conformation Change ===

The conformational change of NTCP's core domain helices are essential to bile salt binding and uptake. Helices 3 and 8 <scene name='95/952711/X_motif/1'>of the X motif</scene> are the main structural components of the conformational change, as the X motif has highly conserved polar residue motifs that reside near the bile salt transport sites.. The conformational change is energized by the movement of Na+ down its concentration gradient. Before bile salt can bind, the pore in which salt binds must be <scene name='95/952711/Open_pore_ntcp_non_transparent/1'>open</scene>. Conserved glycine and proline residues act as hinges in the connecting short loops, intracellular α-helices, and extracellular α-helices of NTCP to facilitate the movement of the core and panel domain to allow for a conformational change. The <scene name='95/952711/Open_pore_ntcp/1'>open</scene> pore is flipped toward the outer membrane to allow for bile salt binding by exposing the Na+ binding sites and the X motif within NTCP. Once <scene name='95/952711/Open_pore_with_bile_salts/1'>bound</scene>, the pore is <scene name='95/952711/Closed_pore_ntcp/1'>closed</scene>, and bile salt is able to be released into the cell, past the inner membrane.

The conformational change of NTCP's core domain helices are essential to bile salt binding and uptake. Helices 3 and 8 <scene name='95/952711/X_motif/1'>of the X motif</scene> are the main structural components of the conformational change, as the X motif has highly conserved polar residue motifs that reside near the bile salt transport sites.. The conformational change is energized by the movement of Na+ down its concentration gradient. Before bile salt can bind, the pore in which salt binds must be <scene name='95/952711/Open_pore_ntcp_non_transparent/1'>open</scene>. Conserved glycine and proline residues act as hinges in the connecting short loops, intracellular α-helices, and extracellular α-helices of NTCP to facilitate the movement of the core and panel domain to allow for a conformational change. The <scene name='95/952711/Open_pore_ntcp/1'>open</scene> pore is flipped toward the outer membrane to allow for bile salt binding by exposing the Na+ binding sites and the X motif within NTCP. Once <scene name='95/952711/Open_pore_with_bile_salts/1'>bound</scene>, the pore is <scene name='95/952711/Closed_pore_ntcp/1'>closed</scene>, and bile salt is able to be released into the cell, past the inner membrane. (Goutam)

=== Mechanism ===

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 NTCP has 9 transmembrane alpha helices (TM) that form the protein, with an extracellular N-terminus and intracellular C-terminus. NTCP has two domains within the protein, <scene name='95/952711/Panel_domain/1'>a panel domain</scene>, made up of TM1, TM5, and TM6, and <scene name='95/952711/Core_domain/3'>a core domain</scene>, made up of TM2-4 and TM7-9. An interesting feature of NTCP is the cross of TM3 and TM8 that form an <scene name='95/952711/X_motif/1'>X motif</scene> within the protein that is used in the conformational change of NTCP. The two domains are essential to the conformation change of NTCP to bind bile salts <Ref name="Xiangbing"> Xiangbing Qi, Wenhui Li. (2022). Unlocking the secrets to human NTCP structure. The Innovation, Vol. 3, Issue 5. 100294, ISSN 2666-6758, [https://doi.org/10.1016/j.xinn.2022.100294 DOI: 10.1016/j.xinn.2022.100294]. </Ref>.
-There are two significant patches in the NTCP structure that facilitate ligand binding. Residues 84-87 of NTCP are Patch 1, which are located on the TM2-TM3 loop in the core domain. This patch is also considered the extracellular region of the binding tunnel within NTCP. Residues 157-165 of NTCP are associated with <scene name='95/952711/Binding_site_2_with_surface/1'>Patch 2</scene>. They are located on the N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in the extracellular region of the binding tunnel. These residues' importance was determined through mutations of these residues and examined through pull-down assays <ref name="Asami"/>. The pre-S1 domain of HBV/HDV binds to the patches on NTCP in order to transport the virus from the exterior of NTCP to the interior binding tunnel to infect human liver cells.
+There are two significant patches in the NTCP structure that facilitate ligand binding. Residues 84-87 of NTCP are Patch 1, which are located on the TM2-TM3 loop in the core domain. This patch is also considered the extracellular region of the binding tunnel within NTCP. Residues 157-165 of NTCP are associated with <scene name='95/952711/Binding_site_2_with_surface/1'>Patch 2</scene>. They are located on the N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in the extracellular region of the binding tunnel. These residues' importance was determined through mutations of these residues and examined through pull-down assays <ref name="Asami"/>. The pre-S1 domain of HBV/HDV binds to the patches on NTCP in order to transport the virus from the exterior of NTCP to the interior binding tunnel to infect human liver cells. (Goutam)
 [[Image:Figuredomain.png|450 px|right|thumb|'''Figure 3.''' Cartoon of NTCP topology.]]
@@ Line 30: / Line 30: @@
 === Conformation Change ===
-The conformational change of NTCP's core domain helices are essential to bile salt binding and uptake. Helices 3 and 8 <scene name='95/952711/X_motif/1'>of the X motif</scene> are the main structural components of the conformational change, as the X motif has highly conserved polar residue motifs that reside near the bile salt transport sites.. The conformational change is energized by the movement of Na+ down its concentration gradient. Before bile salt can bind, the pore in which salt binds must be <scene name='95/952711/Open_pore_ntcp_non_transparent/1'>open</scene>. Conserved glycine and proline residues act as hinges in the connecting short loops, intracellular α-helices, and extracellular α-helices of NTCP to facilitate the movement of the core and panel domain to allow for a conformational change. The  <scene name='95/952711/Open_pore_ntcp/1'>open</scene> pore is flipped toward the outer membrane to allow for bile salt binding by exposing the Na+ binding sites and the X motif within NTCP. Once  <scene name='95/952711/Open_pore_with_bile_salts/1'>bound</scene>, the pore is <scene name='95/952711/Closed_pore_ntcp/1'>closed</scene>, and bile salt is able to be released into the cell, past the inner membrane.
+The conformational change of NTCP's core domain helices are essential to bile salt binding and uptake. Helices 3 and 8 <scene name='95/952711/X_motif/1'>of the X motif</scene> are the main structural components of the conformational change, as the X motif has highly conserved polar residue motifs that reside near the bile salt transport sites.. The conformational change is energized by the movement of Na+ down its concentration gradient. Before bile salt can bind, the pore in which salt binds must be <scene name='95/952711/Open_pore_ntcp_non_transparent/1'>open</scene>. Conserved glycine and proline residues act as hinges in the connecting short loops, intracellular α-helices, and extracellular α-helices of NTCP to facilitate the movement of the core and panel domain to allow for a conformational change. The  <scene name='95/952711/Open_pore_ntcp/1'>open</scene> pore is flipped toward the outer membrane to allow for bile salt binding by exposing the Na+ binding sites and the X motif within NTCP. Once  <scene name='95/952711/Open_pore_with_bile_salts/1'>bound</scene>, the pore is <scene name='95/952711/Closed_pore_ntcp/1'>closed</scene>, and bile salt is able to be released into the cell, past the inner membrane. (Goutam)
 === Mechanism ===