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==== Bile Salt ==== | ==== Bile Salt ==== | ||
The <scene name='95/952721/Amphipathic_patterns/2'>amphipathic pore</scene> is also characteristic of NTCP. The pore surface remains {{Template:ColorKey_Hydrophobic}}, while lining of the open pore state is largely {{Template:ColorKey_Polar}}. However, in the "inward-facing conformation" the polar pore residues are inaccessible. When the pore is closed only the surface hydrophobic residues are observed. As the pore opens up inner polar residues become accessible allowing for the binding of substrates. The pattern of hydrophobic and polar residues within the pore is believed to follow similar amphipathic patterns within taurocholate and other NTCP substrates, such as [https://en.wikipedia.org/wiki/Steroid steroids] and [https://en.wikipedia.org/wiki/Thyroid_hormones thyroid hormones]. <Ref name = Qi> Qi X. and Li W. (2022). Unlocking the secrets to human NTCP structure. The Innovation 3(5), 100294. https://doi.org/10.1016/j.xinn.2022.100294 </ref> Thus the channel provides specificity while preventing leakage of other substrates. When observing the relevant <scene name='95/952722/Bile_salts_res/1'>bile salt binding residues</scene> it is shown that some residues form Van der Waals interactions while others will form dipole-dipole or ionic interactions with bile salt substrates. The core domain appears to contribute most of the polar domains, while the panel domain contributes more hydrophobic residues. | The <scene name='95/952721/Amphipathic_patterns/2'>amphipathic pore</scene> is also characteristic of NTCP. The pore surface remains {{Template:ColorKey_Hydrophobic}}, while lining of the open pore state is largely {{Template:ColorKey_Polar}}. However, in the "inward-facing conformation" the polar pore residues are inaccessible. When the pore is closed only the surface hydrophobic residues are observed. As the pore opens up inner polar residues become accessible allowing for the binding of substrates. The pattern of hydrophobic and polar residues within the pore is believed to follow similar amphipathic patterns within taurocholate and other NTCP substrates, such as [https://en.wikipedia.org/wiki/Steroid steroids] and [https://en.wikipedia.org/wiki/Thyroid_hormones thyroid hormones]. <Ref name = Qi> Qi X. and Li W. (2022). Unlocking the secrets to human NTCP structure. The Innovation 3(5), 100294. https://doi.org/10.1016/j.xinn.2022.100294 </ref> Thus the channel provides specificity while preventing leakage of other substrates. When observing the relevant <scene name='95/952722/Bile_salts_res/1'>bile salt binding residues</scene> it is shown that some residues form Van der Waals interactions while others will form dipole-dipole or ionic interactions with bile salt substrates. The core domain appears to contribute most of the polar domains, while the panel domain contributes more hydrophobic residues. | ||
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| - | === Conformational Change === | ||
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== Bile Salt Transport == | == Bile Salt Transport == | ||
| - | A proposed pathway for NTCP bile salt transport suggests that both sodium ions are translocated with the transport of one bile salt.<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 </Ref> Initally all <scene name='95/952721/Mech_step_1/1'>ligands and sodium ions are bound</scene> then both sodium ions are released along with the inner bile salt into the cytoplasm (Fig. 5). The <scene name='95/952721/Mech_step_2/2'>outermost bile salt remains bound</scene> however in the pore, likely helping to prevent leakage <Ref name = "Liu"> The movement of sodium ions then facilitates the conformational change to the inward-facing, pore inaccessible conformation that is believed to <scene name='95/952721/Mech_step_3/1'>displace the outer bile salt</scene> into the inner bile salt placement (Fig. 5). </Ref name = "Liu"> Sodium ions then bind to NTCP, favoring the open-pore state and also allowing for the binding of another outer bile salt (Fig 5). The process can then start again releasing the next inner bile salt with the translocation of the sodium ions into the cytoplasm. | + | A proposed pathway for NTCP bile salt transport suggests that both sodium ions are translocated with the transport of one bile salt.<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 </Ref> Initally all <scene name='95/952721/Mech_step_1/1'>ligands and sodium ions are bound</scene> then both sodium ions are released along with the inner bile salt into the cytoplasm (Fig. 5). The <scene name='95/952721/Mech_step_2/2'>outermost bile salt remains bound</scene> however in the pore, likely helping to prevent leakage <Ref name = "Liu"> The movement of sodium ions then facilitates the conformational change to the inward-facing, pore inaccessible conformation that is believed to <scene name='95/952721/Mech_step_3/1'> displace the outer bile salt</scene> into the inner bile salt placement (Fig. 5). </Ref name = "Liu"> Sodium ions then bind to NTCP, favoring the open-pore state and also allowing for the binding of another outer bile salt (Fig 5). The process can then start again releasing the next inner bile salt with the translocation of the sodium ions into the cytoplasm. |
== HBV Binding == | == HBV Binding == | ||
Revision as of 17:00, 6 April 2023
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Sodium Bile Salt Co-Transporting Protein
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References
- ↑ Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol. 2011;(201):205-59. doi: 10.1007/978-3-642-14541-4_5. PMID: 21103971. DOI: DOI: 10.1007/978-3-642-14541-4_5.
- ↑ Anwer MS, Stieger B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 2014 Jan;466(1):77-89. PMID:24196564 doi:10.1007/s00424-013-1367-0
- ↑ Park, JH., Iwamoto, M., Yun, JH. et al. Structural insights into the HBV receptor and bile acid transporter NTCP. Nature 606, 1027–1031 (2022). https://doi.org/10.1038/s41586-022-04857-0.
- ↑ 4.0 4.1 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.
- ↑ Qi X. and Li W. (2022). Unlocking the secrets to human NTCP structure. The Innovation 3(5), 100294. https://doi.org/10.1016/j.xinn.2022.100294
- ↑ 6.0 6.1 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
