Sandbox PgpWWC
From Proteopedia
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==P-glycoprotein (ABCB1)== | ==P-glycoprotein (ABCB1)== | ||
| - | <StructureSection load='4q9h' size='340' side='right' caption=' | + | <StructureSection load='4q9h' size='340' side='right' caption='ABCB1: 3.4 Å resolution 'scene=''> |
| - | '''P-glycoprotein (P-gp, ABCB1)''' is an ATP binding casette transporter that hydrolyses ATP for conformational changes after a variety of substrates are transported. It is one of the membrane proteins responsible for the multi drug resistance (MDR) in cancer treatment, as well as various other drug therapies.<ref>Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.</ref><ref>He, L., & Liu, G. Q. (2002). Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacologica Sinica, 23(7), 591-596</ref> | + | '''P-glycoprotein (P-gp, ABCB1)''' is an ATP binding casette transporter that hydrolyses ATP for conformational changes after a variety of substrates are transported. It is one of the membrane proteins responsible for the multi drug resistance (MDR) in cancer treatment, as well as various other drug therapies.<ref>Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.</ref><ref>He, L., & Liu, G. Q. (2002). Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacologica Sinica, 23(7), 591-596</ref> ABCB1 can be found in tumor cells, as well as in the liver, kidney, adrenal gland, intestine, blood-brain barrier (BBB), placenta, blood-testis barrier, and blood-ovarian barriers. An effective MDR transport protein, the high amount of active ABCB1 substrates stems from the polyspecificity for hydrophobic and aromatic compounds.<ref>Marchetti, S., Mazzanti, R., Beijnen, J. H., & Schellens, J. H. (2007). Concise review: clinical relevance of drug–drug and herb–drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). The Oncologist, 12(8), 927-941.</ref> |
{{Template:ColorKey_Hydrophobic}}, {{Template:ColorKey_Polar}} | {{Template:ColorKey_Hydrophobic}}, {{Template:ColorKey_Polar}} | ||
<scene name='69/699852/Hydrophobic_residues/4'>Here</scene> | <scene name='69/699852/Hydrophobic_residues/4'>Here</scene> | ||
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== Structure == | == Structure == | ||
| + | ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure. The entrance of substrate into the structure is argued to occur with a cavity in the lipid bilayer.<ref>Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.</ref> When a substrate binds to the binding site, a conformational change causes a scissor-like action that causes the protein to open to the outside of the cell, releasing the substrate. ATP is then hydrolyzed to re-induce the inward-facing conformation in preparation for the binding of another substrate compound from the bilayer.<ref>Chufan, E. E., Sim, H. M., & Ambudkar, S. V. (2014). Chapter Three – Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies. Advances in Cancer Research, 125, 71-96</ref> This efflux of substrate out of the cell prevents the accumulation of potentially toxic xenobiotics; however, this effective expulsion of a wide variety of substrates caused the multi-drug resistance. | ||
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| + | The polyspecificity of ABCB1 is often attributed to a large internal cavity of ~6,000 Å that can transport up to two compounds simultaneously ranging from sizes of 330-4,000 Da. Three binding sites have been proposed, including the H (Hoescht), R (rhodamine), and the P (prazosin and progesterone) sites. <ref>Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.</ref> | ||
== Clinical Relevance == | == Clinical Relevance == | ||
Revision as of 19:56, 23 April 2015
P-glycoprotein (ABCB1)
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References
- ↑ Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.
- ↑ He, L., & Liu, G. Q. (2002). Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacologica Sinica, 23(7), 591-596
- ↑ Marchetti, S., Mazzanti, R., Beijnen, J. H., & Schellens, J. H. (2007). Concise review: clinical relevance of drug–drug and herb–drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). The Oncologist, 12(8), 927-941.
- ↑ Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.
- ↑ Chufan, E. E., Sim, H. M., & Ambudkar, S. V. (2014). Chapter Three – Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies. Advances in Cancer Research, 125, 71-96
- ↑ Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., . . . Chang, G. (2009). Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323(5922), 1718-1722.
