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, with two | ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure, with two transmembrane <scene name='69/699852/2_chains/1'>chains</scene>. Recent research suggests that multiple portals allow the entrance of substrates from the cytoplasm<ref name="Wolking"> and the lipid bilayer, since the hydrophobic substrates can partition into the membrane.<ref name="Aller"<ref /> 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 from the cytoplasm is then hydrolyzed for active transport of the drugs against a concentration gradient, and ATP is again 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.<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. Retrieved April 2015, from Science Direct.</ref> Three binding sites were originally proposed by Aller et al.,<ref name="Aller"/> which includes the H (Hoescht), R (rhodamine), and P (prazosin and progesterone) sites. Since multiple substrates can be transported simultaneously, the binding of substrate to one site can stimulate the transport in the other sites. For example, the substrate binding on the P site stimulates transport at the R and H sites. The P site was recently renamed the M (Modulatory) site.<ref name="Zeino">PMID: 2474833</ref> However, these regions signify areas of residues that interact with substrates, while binding sites and the corresponding residue interactions are specific for different substrates transported. This specific affinity suggests primary and secondary sites that overlap.<ref name="Aller" /> | 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.<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. Retrieved April 2015, from Science Direct.</ref> Three binding sites were originally proposed by Aller et al.,<ref name="Aller"/> which includes the H (Hoescht), R (rhodamine), and P (prazosin and progesterone) sites. Since multiple substrates can be transported simultaneously, the binding of substrate to one site can stimulate the transport in the other sites. For example, the substrate binding on the P site stimulates transport at the R and H sites. The P site was recently renamed the M (Modulatory) site.<ref name="Zeino">PMID: 2474833</ref> However, these regions signify areas of residues that interact with substrates, while binding sites and the corresponding residue interactions are specific for different substrates transported. This specific affinity suggests primary and secondary sites that overlap.<ref name="Aller" /> | ||