ABCG2 multidrug transporter: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

R. Jeremy Johnson, Michal Harel, Karsten Theis

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 ==Background==
-The [https://en.wikipedia.org/wiki/ABCG2 ABCG2 multidrug transporter] is a membrane protein from the '''A'''TP-'''B'''inding '''C'''assette [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter (ABC)] transporter family, specifically the G-subfamily. Also known as the breast cancer resistance protein (BCRP), ABCG2 has physiological roles in various tissue cells including the [https://en.wikipedia.org/wiki/Mammary_gland mammary gland] and the [https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier blood-brain], [https://en.wikipedia.org/wiki/Blood%E2%80%93testis_barrier blood-testis], and [https://en.wikipedia.org/wiki/Placenta maternal-fetal] barriers.<ref name="Taylor">PMID:28554189</ref>  ABCG2 protects cells by exporting [https://en.wikipedia.org/wiki/Xenobiotic xenobiotic] molecules out of the cell using ATP hydrolysis. ABCG2 also affects the [https://en.wikipedia.org/wiki/Pharmacokinetics pharmacokinetics] of many drugs and contributes to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance].<ref name="Manolaridis">PMID:30405239</ref> ABCG2 belongs to the family of 48 transporter proteins called ATP-binding cassette transporters (ABC transporters). A high percentage of the ABC family transporters (19 of the 48) transport [https://en.wikipedia.org/wiki/List_of_chemotherapeutic_agents chemotherapeutic agents] out of cells, making expression levels of ABC transporters a major indicator of cancer treatment prognosis.<ref name="Robey">PMID:29643473</ref>
+The [https://en.wikipedia.org/wiki/ABCG2 ABCG2 multidrug transporter] or '''abc subfamily G member 2''' is a membrane protein from the '''A'''TP-'''B'''inding '''C'''assette [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter (ABC)] transporter family, specifically the G-subfamily. Also known as the breast cancer resistance protein (BCRP), ABCG2 has physiological roles in various tissue cells including the [https://en.wikipedia.org/wiki/Mammary_gland mammary gland] and the [https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier blood-brain], [https://en.wikipedia.org/wiki/Blood%E2%80%93testis_barrier blood-testis], and [https://en.wikipedia.org/wiki/Placenta maternal-fetal] barriers.<ref name="Taylor">PMID:28554189</ref>  ABCG2 protects cells by exporting [https://en.wikipedia.org/wiki/Xenobiotic xenobiotic] molecules out of the cell using ATP hydrolysis. ABCG2 also affects the [https://en.wikipedia.org/wiki/Pharmacokinetics pharmacokinetics] of many drugs and contributes to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance].<ref name="Manolaridis">PMID:30405239</ref> ABCG2 belongs to the family of 48 transporter proteins called ATP-binding cassette transporters (ABC transporters). A high percentage of the ABC family transporters (19 of the 48) transport [https://en.wikipedia.org/wiki/List_of_chemotherapeutic_agents chemotherapeutic agents] out of cells, making expression levels of ABC transporters a major indicator of cancer treatment prognosis.<ref name="Robey">PMID:29643473</ref>
 Using [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryoelectron microscopy] (cryo-EM), the two cavity substrate transport structure (<scene name='83/832932/Highlight_cavity_1/3'>Cavity 1</scene>; <scene name='83/832932/Atp_bound_use_cav_2/3'>Cavity 2</scene>), inward facing nucleotide binding domain (<scene name='83/832932/Overall_structure_nbd_unbound/6'>NBD</scene>), and condensed extracellular loop 3 (<scene name='83/832939/El-3/3'>EL-3</scene>) structure of ABCG2 have been elucidated. These structures also illustrated the transporter cycle of ABCG2, the binding locations for inhibitors, and the link between cancer and the ABC transporter family.<ref name="Taylor"/><ref name="Manolaridis"/><ref name="Jackson">PMID:29610494</ref>
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 When ATP binds, α-helices in the NBD <scene name='83/832932/Atp_bound_nbd/3'>rotate</scene> approximately 35° relative to the <scene name='83/832932/Overall_structure_nbd_unbound/5'>inward-facing conformation of NBD</scene>. This shift in the NBD causes slight shifts of α-helices in the TMD; these helices are <scene name='83/832932/Atp_bound_use_tmd/4'>pushed toward each other</scene> relative to the <scene name='83/832932/Overall_structure_tmd_unbound/4'>inward-facing conformation of TMD</scene>. The overall shift from inward-facing to outward-facing promotes the transport of substrates through the transporter.<ref name="Manolaridis"/>
+How the movement of the NBDs is linked to the movement of the transdomain movements is nicely visible in this <scene name='86/869419/Animation/2'>superposition</scene>.{{Template:Button Toggle Animation2}}
 The NBDs in ABCG2 remain in contact with one another even without a bound substrate, providing greater substrate specificity as the entrance to the transporter is not as globular as other ABC transporters like ABCB1 or ABCC1. The entrance from the cytoplasm to the transporter is lined by [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] residues<scene name='83/832939/Lining_of_entrance_of_nbd/1'> A397, V401, L405, L539, I543 and T547</scene> in both [https://en.wikipedia.org/wiki/Monomer monomers].