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Multidrug Transporter ABCG2 in Homo Sapiens

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Introduction

Function

[1]

ABCG2 transports a variety of substrates, particularly flat, hydrophobic, and/or polycylic molecules. It is found in different biological membranes, such as the blood-brain barrier (BBB), blood-testis barrier, and the blood-placental barrier. It is thought to help protect those tissues and many others from cytotoxins. In addition to cytotoxin protection, ABCG2 secretes endogenous substrates in the adrenal gland, excretes toxins in the liver and kidneys, and regulates absorption of substrates.

Disease

Relevance

Structural highlights

Nature_Structural_&_Molecular_Biology_Vol_25 [2]

Multidrug Transporter ABCG2 is a dimer that consists of two cavities separated by a leucine plug. Cavity 1 is a binding pocket open to the cytoplasm and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates. Many of its amino acids residues form hydrophobic interactions with the bound substrate, as shown in green in Figure 1. Cavity 2 is located above the leucine plug. It is empty until a magnesium ion and ATP are bound to ABCG2. inter- and intra-disulfides promote the release of the substrate from the cavity into the extracellular space.

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:https://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

References

^[1] ^[2] ^[3] ^[4]

↑ Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:https://dx.doi.org/10.1002/1873-3468.12677
↑ Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NMI, Bause M, Bauer S, Bartholomaeus R, Bernhardt G, Koenig B, Buschauer A, Stahlberg H, Altmann KH, Locher KP. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat Struct Mol Biol. 2018 Apr;25(4):333-340. doi: 10.1038/s41594-018-0049-1. Epub, 2018 Apr 2. PMID:29610494 doi:https://dx.doi.org/10.1038/s41594-018-0049-1
↑ Manolaridis I, Jackson SM, Taylor NMI, Kowal J, Stahlberg H, Locher KP. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature. 2018 Nov;563(7731):426-430. doi: 10.1038/s41586-018-0680-3. Epub 2018 Nov, 7. PMID:30405239 doi:https://dx.doi.org/10.1038/s41586-018-0680-3
↑ Fetsch PA, Abati A, Litman T, Morisaki K, Honjo Y, Mittal K, Bates SE. Localization of the ABCG2 mitoxantrone resistance-associated protein in normal tissues. Cancer Lett. 2006 Apr 8;235(1):84-92. doi: 10.1016/j.canlet.2005.04.024. Epub, 2005 Jun 28. PMID:15990223 doi:https://dx.doi.org/10.1016/j.canlet.2005.04.024

Student Contributors

Shelby Skaggs

[1] Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:https://dx.doi.org/10.1002/ijch.201300024

[2] Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

[Ransey-1] Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:https://dx.doi.org/10.1002/1873-3468.12677

[Jackson-2] Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NMI, Bause M, Bauer S, Bartholomaeus R, Bernhardt G, Koenig B, Buschauer A, Stahlberg H, Altmann KH, Locher KP. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat Struct Mol Biol. 2018 Apr;25(4):333-340. doi: 10.1038/s41594-018-0049-1. Epub, 2018 Apr 2. PMID:29610494 doi:https://dx.doi.org/10.1038/s41594-018-0049-1

[Manolaridis-3] Manolaridis I, Jackson SM, Taylor NMI, Kowal J, Stahlberg H, Locher KP. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature. 2018 Nov;563(7731):426-430. doi: 10.1038/s41586-018-0680-3. Epub 2018 Nov, 7. PMID:30405239 doi:https://dx.doi.org/10.1038/s41586-018-0680-3

[Fetsch-4] Fetsch PA, Abati A, Litman T, Morisaki K, Honjo Y, Mittal K, Bates SE. Localization of the ABCG2 mitoxantrone resistance-associated protein in normal tissues. Cancer Lett. 2006 Apr 8;235(1):84-92. doi: 10.1016/j.canlet.2005.04.024. Epub, 2005 Jun 28. PMID:15990223 doi:https://dx.doi.org/10.1016/j.canlet.2005.04.024

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@@ Line 6: / Line 6: @@
 == Introduction ==
 == Function ==
@@ Line 21: / Line 22: @@
 [https://www.nature.com/articles/s41586-018-0680-3]
-Multidrug Transporter ABCG2 is a <scene name='83/832937/Dimer/1'>dimer</scene> that consists of two cavities separated by a <scene name='83/832937/Leucine_plug/3'>leucine plug</scene>. Cavity 1 is a binding pocket open to the cytoplasm and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates. Many of its amino acids residues form hydrophobic interactions with the bound substrate, as shown in green in '''Figure 1'''.  Cavity 2 is located above the leucine plug. It is empty until a <scene name='83/832937/Atp_and_mg_bound_to_abcg2/3'>magnesium ion and ATP</scene> are bound to ABCG2. Its <scene name='83/832937/Cysteine_disulfide_bridges/4'>inter- and intra-disulfides</scene> promote the release of the substrate from the cavity into the extracellular space.
+Multidrug Transporter ABCG2 is a <scene name='83/832937/Dimer/1'>dimer</scene> that consists of two cavities separated by a <scene name='83/832937/Leucine_plug/4'>leucine plug</scene>. Cavity 1 is a binding pocket open to the cytoplasm and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates. Many of its amino acids residues form hydrophobic interactions with the bound substrate, as shown in green in '''Figure 1'''.  Cavity 2 is located above the leucine plug. It is empty until a <scene name='83/832937/Atp_and_mg_bound_to_abcg2/4'>magnesium ion and ATP</scene> are bound to ABCG2. <scene name='83/832937/Cysteine_disulfide_bridges/5'>inter- and intra-disulfides</scene> promote the release of the substrate from the cavity into the extracellular space.
 </StructureSection>

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Latest revision as of 05:37, 21 April 2020

Multidrug Transporter ABCG2 in Homo Sapiens

Contents

Introduction

Function

Disease

Relevance

Structural highlights

References

Student Contributors

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