Sandbox Reserved 1613: Difference between revisions

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==Introduction==

[[Image:ABCG2 DimerPic NoWatermark.png|400 px|right|thumb|Figure 1: Multidrug-transporter ABCG2 is a dimer.]]

[[Image:ABCG2 DimerPic NoWatermark.png|400 px|right|thumb|Figure 1: Multidrug-transporter ABCG2 is a dimer (6ffc).]]

The ABCG2 transporter protein is a notable [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein]. It transports [https://en.wikipedia.org/wiki/Xenobiotic xenobiotic] material out of cells in many tissues. ABCG2 belongs to the family of 48 transporter proteins called ATP-binding cassette transporters (ABC transporters). The ABC transporters differ from each other by their size structure, and ordering of domains. Ample evidence has shown a link between [https://en.wikipedia.org/wiki/Multiple_drug_resistance multi-drug resistance] and the presence of ABC transporters in the plasma membrane of cells. This is important as multi-drug resistance is one of the major indicators of bad prognoses in cancer treatment. In fact, 19 of the 48 transporters of the ABC family have been shown to transport [https://en.wikipedia.org/wiki/List_of_chemotherapeutic_agents chemotherapeutic agents] out of cells.<ref name="Robey">PMID:29643473</ref> In recent studies, with [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryogenic electronic microscopy] (Cryo EM), the unique <scene name='83/832939/2_cavities/1'>two cavity substrate transport structure</scene>, inward facing nucleotide binding domain and <scene name='83/832939/El-3/3'>condensed EL-3 structure</scene> of ABCG2 have been elucidated, among other features. These new discoveries have allowed for progress towards discovering the exact link between cancer and the ABC transporter family and have allowed for more effective drug treatment of cancer. This page will focus on the family of ABC transporters before delving into unique structural features of ABCG2 and finally describing the effects of this transporter on anti-cancer treatment.

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[[Image:Ligand_Interactions_6ffc.png|400 px|right|thumb|Figure 2: MZ29 bound to cavity 1 of ABCG2 (6ffc). Two MZ29 are shown in sticks and are colored by element. Hydrophobic interactions between the surface of cavity 1 and MZ29 are shown in green.]]

Multidrug Transporter ABCG2 is a <scene name='83/832937/Dimer/1'>dimer</scene> that consists of two [https://en.wikipedia.org/wiki/Cavity cavities] separated by a <scene name='83/832937/Leucine_plug/4'>leucine plug</scene>. Cavity 1 is a binding pocket open to the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates.<ref name="Manolaridis">PMID:30405239</ref> 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. Its <scene name='83/832937/Cysteine_disulfide_bridges/5'>inter- and intra-disulfides</scene> (yellow is inter- and intra-molecular disulfides, golden is intra-molecular only) 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 [https://en.wikipedia.org/wiki/Cavity cavities] separated by a <scene name='83/832937/Leucine_plug/4'>leucine plug</scene>. Cavity 1 is a binding pocket open to the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates.<ref name="Manolaridis">PMID:30405239</ref> 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.<ref name=" Its <scene name='83/832937/Cysteine_disulfide_bridges/5'>inter- and intra-disulfides</scene> (yellow is inter- and intra-molecular disulfides, golden is intra-molecular only) promote the release of the substrate from the cavity into the extracellular space.

One interesting feature of the NBD's is the fact that they remain in contact with one another even without a bound substrate. This makes the ABCG2 transporter unique and provides greater substrate specificity as the entrance to the transporter is not as globular as either ABCB1 or ABCC1. The entrance from the cytoplasm to the transporter is a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] membrane entrance lined by <scene name='83/832939/Lining_of_entrance_of_nbd/1'>residues A397, V401, L405, L539, I543 and T547</scene> in both [https://en.wikipedia.org/wiki/Monomer monomers].

Dimerization of ABCG2 was originally thought to be achieved with the help of the <scene name='83/832939/Disproved_dimerization_process/1'>406xxx410 structural motif</scene> in each of the two domains but Cryo-EM showed that the [https://en.wikipedia.org/wiki/Sequence_motif motifs] were on opposite sides of the protein.

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@@ Line 2: / Line 2: @@
 <StructureSection load='6ffc' size='350' frame='true' side='right' caption='Figure 1: ABCG2 6FFC' scene=’’>
 ==Introduction==
-[[Image:ABCG2 DimerPic NoWatermark.png|400 px|right|thumb|Figure 1: Multidrug-transporter ABCG2 is a dimer.]]
+[[Image:ABCG2 DimerPic NoWatermark.png|400 px|right|thumb|Figure 1: Multidrug-transporter ABCG2 is a dimer (6ffc).]]
 The ABCG2 transporter protein is a notable [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein]. It transports [https://en.wikipedia.org/wiki/Xenobiotic xenobiotic] material out of cells in many tissues. ABCG2 belongs to the family of 48 transporter proteins called ATP-binding cassette transporters (ABC transporters). The ABC transporters differ from each other by their size structure, and ordering of domains. Ample evidence has shown a link between [https://en.wikipedia.org/wiki/Multiple_drug_resistance multi-drug resistance] and the presence of ABC transporters in the plasma membrane of cells. This is important as multi-drug resistance is one of the major indicators of bad prognoses in cancer treatment. In fact, 19 of the 48 transporters of the ABC family have been shown to transport [https://en.wikipedia.org/wiki/List_of_chemotherapeutic_agents chemotherapeutic agents] out of cells.<ref name="Robey">PMID:29643473</ref> In recent studies, with [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryogenic electronic microscopy] (Cryo EM), the unique <scene name='83/832939/2_cavities/1'>two cavity substrate transport structure</scene>, inward facing nucleotide binding domain and <scene name='83/832939/El-3/3'>condensed EL-3 structure</scene> of ABCG2 have been elucidated, among other features. These new discoveries have allowed for progress towards discovering the exact link between cancer and the ABC transporter family and have allowed for more effective drug treatment of cancer. This page will focus on the family of ABC transporters before delving into unique structural features of ABCG2 and finally describing the effects of this transporter on anti-cancer treatment.
@@ Line 15: / Line 15: @@
 [[Image:Ligand_Interactions_6ffc.png|400 px|right|thumb|Figure 2: MZ29 bound to cavity 1 of ABCG2 (6ffc). Two MZ29 are shown in sticks and are colored by element. Hydrophobic interactions between the surface of cavity 1 and MZ29 are shown in green.]]
-Multidrug Transporter ABCG2 is a <scene name='83/832937/Dimer/1'>dimer</scene> that consists of two [https://en.wikipedia.org/wiki/Cavity cavities] separated by a <scene name='83/832937/Leucine_plug/4'>leucine plug</scene>. Cavity 1 is a binding pocket open to the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates.<ref name="Manolaridis">PMID:30405239</ref> 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. Its <scene name='83/832937/Cysteine_disulfide_bridges/5'>inter- and intra-disulfides</scene> (yellow is inter- and intra-molecular disulfides, golden is intra-molecular only) 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 [https://en.wikipedia.org/wiki/Cavity cavities] separated by a <scene name='83/832937/Leucine_plug/4'>leucine plug</scene>. Cavity 1 is a binding pocket open to the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and the inner leaflet of the plasma membrane. Its shape is suitable to bind flat, hydrophobic and polycyclic substrates.<ref name="Manolaridis">PMID:30405239</ref> 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.<ref name=" Its <scene name='83/832937/Cysteine_disulfide_bridges/5'>inter- and intra-disulfides</scene> (yellow is inter- and intra-molecular disulfides, golden is intra-molecular only) promote the release of the substrate from the cavity into the extracellular space.
 One interesting feature of the NBD's is the fact that they remain in contact with one another even without a bound substrate. This makes the ABCG2 transporter unique and provides greater substrate specificity as the entrance to the transporter is not as globular as either ABCB1 or ABCC1. The entrance from the cytoplasm to the transporter is a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] membrane entrance lined by <scene name='83/832939/Lining_of_entrance_of_nbd/1'>residues A397, V401, L405, L539, I543 and T547</scene> in both [https://en.wikipedia.org/wiki/Monomer monomers].
 Dimerization of ABCG2 was originally thought to be achieved with the help of the <scene name='83/832939/Disproved_dimerization_process/1'>406xxx410 structural motif</scene> in each of the two domains but Cryo-EM showed that the [https://en.wikipedia.org/wiki/Sequence_motif motifs] were on opposite sides of the protein.