Sandbox PgpWWC: Difference between revisions
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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 from a cavity in the lipid bilayer.<ref name="Aller" /> When a substrate binds to the binding site, a conformational change | 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 from a cavity in the lipid bilayer.<ref name="Aller" /> When a substrate binds to the binding site, a conformational change 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 causes the multi-drug resistance. | ||
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 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 P (prazosin and progesterone) sites.<ref name="Aller" /> | ||
== Clinical Relevance == | == Clinical Relevance == | ||
Revision as of 23:45, 23 April 2015
P-glycoprotein (ABCB1)P-glycoprotein (ABCB1)
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.[1][2] 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.[3] Hydrophobic, Polar Gottesman, M. M., Pastan, I., & Ambudkar, S. V. (1996). P-glycoprotein and multidrug resistance. Current opinion in genetics & development, 6(5), 610-617. HistoryStructureABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure. The entrance of substrate into the structure is argued to occur from a cavity in the lipid bilayer.[1] When a substrate binds to the binding site, a conformational change 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.[4] 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 causes the multi-drug resistance. 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 P (prazosin and progesterone) sites.[1] Clinical Relevance |
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ReferencesReferences
- ↑ 1.0 1.1 1.2 Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009 Mar 27;323(5922):1718-22. PMID:19325113 doi:323/5922/1718
- ↑ He L, Liu GQ. Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacol Sin. 2002 Jul;23(7):591-6. PMID:12100750
- ↑ Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist. 2007 Aug;12(8):927-41. PMID:17766652 doi:http://dx.doi.org/10.1634/theoncologist.12-8-927
- ↑ 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.