Sandbox PgpWWC: Difference between revisions

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==P-glycoprotein (ABCB1)==
==P-glycoprotein (ABCB1)==
<StructureSection load='4q9h' size='340' side='right' caption='ABCB1: 3.4 Å resolution 'scene=''>
<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>PMID: 19325113</ref><ref>PMID: 12100750</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>PMID: 17766652</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 name="Aller">PMID: 19325113</ref><ref>PMID: 12100750</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>PMID: 17766652</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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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.  
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.  


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>
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 name="Aller" />
 
== Clinical Relevance ==
== Clinical Relevance ==


Revision as of 23:36, 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.

History

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.[4] 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.[5] 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.

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.[1]

Clinical Relevance

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.


ABCB1: 3.4 Å resolution

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ReferencesReferences

  1. ↑ 1.0 1.1 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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.
  5. ↑ 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

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