File:Protein orientation map ABCG2.png

2020-04-18T20:04:04Z

Julia Pomeroy:

Sandbox Reserved 1606

2020-04-18T14:35:16Z

Julia Pomeroy:

{{Sandbox_Reserved_CH462_Biochemistry_II}}
==ABCG2 Multidrug Transporter==

<StructureSection load='5nj3' size='350' side='right' caption='ABCG2 Multidrug Transporter.
Green represents residues in monomer A; Purple represents residues in monomer B. Blue is used to highlight areas of interest in select scenes. (PDB Codes: [https://www.rcsb.org/structure/5NJ3 5NJ3] [https://www.rcsb.org/structure/6HBU 6HBU] [https://www.rcsb.org/structure/6HCO 6HCO] [https://www.rcsb.org/structure/6FFC 6FFC])' scene='83/832932/Overall_structure/2'>

==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"/> 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"/>

== Structural highlights ==
===Overall Structure===
ABCG2 is a homodimer with each monomer containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/6'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/5'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD binds and processes ATP and is located inside of the cell where it is exposed to the cytosol. The TMD is responsible for binding and transporting any foreign substrates and is embedded in the cell membrane and extends into the extracellular region. (Figure 1). [[Image:membrane domains.png|250 px|right|thumb|Figure 1. Orientation of ABCG2 in relation to the cell membrane. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]

===ATP Bound and Unbound Conformations===
As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity, using the energy of ATP hydrolysis to facilitate transport. After substrates bind in the TMD, one molecule of <scene name='83/832932/Atp_bound_use2/3'>ATP binds each NBD</scene> (2 molecules of ATP total) causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/3'>inward-facing conformation</scene> to an <scene name='83/832932/Outward_facing_conformation/4'>outward-facing conformation</scene>. ATP coordinates with various residues and a magnesium ion in the <scene name='83/832932/Atp_bound_in_nbd/2'>binding site of each NBD</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>

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"/>

===Cavities and Leucine Plug===
[[Image:Map_leucine_plug.png|250 px|right|thumb|Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The protein is in the inward-facing conformation with Cavity 1 open to the cytosol for substrate recruitment, the Leucine Plug is intact, and Cavity 2 is completely occluded. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]
Substrates are transported through ABCG2 via two cavities separated by a leucine plug (Figure 2). <scene name='83/832932/Cavity_1_zoom_out/2'>Cavity 1</scene> acts as a multidrug binding pocket and is formed by helices at the interface of the monomers in the TMD. When ATP is not bound to the NBDs, Cavity 1 is <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene> in order to recruit substrates for transport. Cavity 1 is <scene name='83/832932/Cavity_1_narrow_surface/4'>narrow</scene> and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules. Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1.<ref name="Taylor"/>

After substrates bind in Cavity 1, ATP binds each NBD leading to the transporter shifting from inward-facing to outward-facing. The outward-facing conformation results in the <scene name='83/832932/Atp_bound_cavity_2/3'>collapse of Cavity 1</scene> in the TMD in which the cavity is no longer <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene>. This collapse forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.<ref name="Manolaridis"/> <scene name='83/832932/Atp_bound_use_cav_2/2'>Cavity 2</scene>, which is occluded when the protein in is the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.<ref name="Taylor"/> <scene name='83/832932/Atp_bound_use_el_disulfides/3'>Disulfide bonds</scene> in the external loops near the exit of Cavity 2 also help promote substrate release.<ref name="Manolaridis"/> Once Cavity 2 is empty, the protein reverts to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a <scene name='83/832932/Leucine_plug_open_con/7'>leucine plug</scene> which likely acts as a substrate check-point during transport; changes to either of these leucine residues have exhibited an increase in transport and a decrease in substrate specificity.<ref name="Manolaridis"/> After the substrate binds Cavity 1 and ATP molecules bind each NBD, the <scene name='83/832932/Atp_bound_cavsleu/5'>leucine plug opens</scene> to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promote substrate release and conversion to the inward-facing conformation.

==Disease==
Dysfunctions in ABCG2 are linked to [https://en.wikipedia.org/wiki/Hyperuricemia hyperuricemia] which can lead to [https://en.wikipedia.org/wiki/Gout gout], [https://en.wikipedia.org/wiki/Kidney_disease kidney disease], and [https://en.wikipedia.org/wiki/Hypertension hypertension], all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 has been found to correlate with a poor prognosis and treatment outcome of various cancers including breast, ovarian, and lung.<ref name="Jackson"/>

===Cancer===
ABCG2 hinders cancer treatment by contributing to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance] in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. Cancer patients typically show high levels of expression of multiple ABC transporters. For example, [https://en.wikipedia.org/wiki/Acute_myeloid_leukemia acute myeloid leukemia] (AML) has an increased expression of [https://en.wikipedia.org/wiki/P-glycoprotein ABCB1], [https://en.wikipedia.org/wiki/ABCG1 ABCG1], and ABCG2 while childhood AML shows an increased expression in [https://en.wikipedia.org/wiki/ABCA3 ABCA3], ABCB1, [https://en.wikipedia.org/wiki/ABCC3 ABCC3], and ABCG2.<ref name="Marzac"/><ref name="Bartholomae"/> Additionally, pancreatic cancer has shown an upregulation of [https://en.wikipedia.org/wiki/ABCB4 ABCB4], [https://en.wikipedia.org/wiki/ABCB11 ABCB11], [https://en.wikipedia.org/wiki/ABCC1 ABCC1], ABCC3, [https://en.wikipedia.org/wiki/ABCC5 ABCC5], [https://en.wikipedia.org/wiki/ABCC10 ABCC10], and ABCG2.<ref name="Mohelnikova-Duchonova"/>

The substrate specificity among ABC transporters varies, so this protein family can collectively export a wide variety of substrates and, ultimately, a wide variety of anticancer drugs. ABCG2 has been known to export anticancer drugs such [https://en.wikipedia.org/wiki/Methotrexate methotrexate], [https://en.wikipedia.org/wiki/Mitoxantrone mitoxantrone], [https://en.wikipedia.org/wiki/Topotecan topotecan], [https://en.wikipedia.org/wiki/Irinotecan irinotecan], and [https://en.wikipedia.org/wiki/Alvocidib flavopiridol]<ref name="Mao"/>. Due to the high expression of multiple ABC transporters in cancer cells, simultaneous treatment of multiple transporters would likely be necessary for successful cancer treatment.

===Inhibitors===
[[Image:kol143 and mz29 abcg2 inhibitors.png|250 px|right|thumb|Figure 3. (Top) Known ABCG2 Inhibitor Kol143; Red numbers indicate points of alternation in derivates of inhibitors. (Bottom) Derivative of Kol143, MZ29.]]
Due to the potential for ABCG2 inhibition to aid in cancer treatment, efforts have been made to develop specific inhibitors of ABCG2 and other ABC transporters. The ABC transporter ABCB1, also known as multidrug resistance 1 (MDR1), was a therapeutic target in previous studies which produced three generations of MDR1 inhibitors, such as [https://en.wikipedia.org/wiki/Verapamil verapamil], [https://en.wikipedia.org/wiki/Valspodar valspodar], and [https://en.wikipedia.org/wiki/Zosuquidar zosuquidar]; however, many of these inhibitors had neurotoxic effects that discouraged their use as anticancer drugs.<ref name="Leonard"/><ref name="Binkhathlan"/><ref name="Witherspoon"/>

Kol143 (Figure 3) is a compound derived from [https://en.wikipedia.org/wiki/Fumitremorgin fungal toxin fumitremorgin C] (FTC), a selective inhibitor of ABCG2 which exhibits undesirable neurotoxic effects.<ref name="Allen"/> Kol143 was found to be less toxic and more potent than FTC; however, this inhibitor is nonselective toward ABCG2.<ref name="Weidner"/> Various inhibitors were derived from Kol143 with changes made at positions 1 and 2 in Figure 3, which are carbons 3 and 9 respectively. Modifications at these positions prove to affect the inhibitory capacities of compounds. A promising compound which has shown a high degree of potency is the inhibitor MZ29 (Figure 3).<ref name="Jackson"/>

ABCG2 inhibitors, <scene name='83/832932/Inhibitor_bound_cavity_1/2'>such as MZ29</scene>, bind Cavity 1 and act as competitive inhibitors against ABCG2 substrates and show a higher affinity toward the transporter. Depending on the size of the inhibitor, one or two molecules can accommodate binding to the cavity and form <scene name='83/832932/Inhibitor_interactions_cavity1/3'>hydrogen bonds, van der Waals, and stacking interactions</scene> within the binding site.<ref name="Jackson"/> Many inhibitors are too big to be transported via the leucine plug resulting in the "clogging" of the transporter. With inhibitors acting as wedges, ABCG2 is locked in the inward-facing conformation and unable to transport molecules out of the cell.<ref name="Manolaridis"/>
</StructureSection>
== References ==
<ref name="Taylor">PMID:28554189</ref>
<ref name="Manolaridis">PMID:30405239</ref>
<ref name="Robey">PMID:29643473</ref>
<ref name="Jackson">PMID:29610494</ref>
<ref name="Marzac">PMID:21606172</ref>
<ref name="Bartholomae">PMID:26512967</ref>
<ref name="Mohelnikova-Duchonova">PMID:23462326</ref>
<ref name="Mao">PMID:25236865</ref>
<ref name="Leonard">PMID:14530494</ref>
<ref name="Binkhathlan">PMID:23369096</ref>
<ref name="Witherspoon">PMID:9816083</ref>
<ref name="Allen">PMID:12477054</ref>
<ref name="Weidner">PMID:26148857</ref>
<references/>
==Student Contributors==
Julia Pomeroy

2020-04-16T22:32:57Z

Julia Pomeroy:

Sandbox Reserved 1606

2020-04-16T22:28:43Z

Julia Pomeroy:

{{Sandbox_Reserved_CH462_Biochemistry_II}}
==ABCG2 Multidrug Transporter==

<StructureSection load='5nj3' size='350' side='right' caption='ABCG2 Multidrug Transporter.
Green represents residues in monomer A; Purple represents residues in monomer B. Blue is used to highlight areas of interest in select scenes. (PDB Codes: [https://www.rcsb.org/structure/5NJ3 5NJ3] [https://www.rcsb.org/structure/6HBU 6HBU] [https://www.rcsb.org/structure/6HCO 6HCO] [https://www.rcsb.org/structure/6FFC 6FFC])' scene='83/832932/Overall_structure/2'>

==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 know 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"/> 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"/>

== Structural highlights ==
===Overall Structure===
ABCG2 is a homodimer with each monomer containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/6'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/5'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD binds and processes ATP and is located inside of the cell where it is exposed to the cytosol. The TMD is responsible for binding and transporting any foreign substrates and is embedded in the cell membrane and extends into the extracellular region. (Figure 1). [[Image:membrane domains.png|250 px|right|thumb|Figure 1. Orientation of ABCG2 in relation to the cell membrane. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]

===ATP Bound and Unbound Conformations===
As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity, using the energy of ATP hydrolysis to facilitate transport. After substrate bind in the TMD, one molecule of <scene name='83/832932/Atp_bound_use2/3'>ATP binds each NBD</scene> (2 molecules of ATP total) causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/3'>inward-facing conformation</scene> to an <scene name='83/832932/Outward_facing_conformation/4'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>

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/3'>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"/>

<scene name='83/832932/Atp_bound_in_nbd/1'>Text To Be Displayed</scene>
===Cavities and Leucine Plug===
[[Image:Map_leucine_plug.png|250 px|right|thumb|Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The protein is in the inward-facing conformation with Cavity 1 open to the cytosol for substrate recruitment, the Leucine Plug is intact, and Cavity 2 is completely occluded. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]
Substrates are transported through ABCG2 via two cavities separated by a leucine plug (Figure 2). <scene name='83/832932/Cavity_1_zoom_out/2'>Cavity 1</scene> acts as a multidrug binding pocket and is formed by helices at the interface of the monomers in the TMD. When ATP is not bound to the NBDs, Cavity 1 is <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene> in order to recruit substrates for transport. Cavity 1 is <scene name='83/832932/Cavity_1_narrow_surface/4'>narrow</scene> and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules. Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1.<ref name="Taylor"/>

After substrates bind in Cavity 1, ATP binds each NBD leading to the transporter shifting from inward-facing to outward-facing. The outward-facing conformation results in the <scene name='83/832932/Atp_bound_cavity_2/3'>collapse of Cavity 1</scene> in the TMD which closes Cavity 1 to the cytosol and forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.<ref name="Manolaridis"/> <scene name='83/832932/Atp_bound_use_cav_2/2'>Cavity 2</scene>, which is occluded when the protein in is the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.<ref name="Taylor"/> <scene name='83/832932/Atp_bound_use_el_disulfides/3'>Disulfide bonds</scene> in the external loops near the exit of Cavity 2 also help promote substrate release.<ref name="Manolaridis"/> Once Cavity 2 is empty, the protein reverts to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a <scene name='83/832932/Leucine_plug_open_con/7'>leucine plug</scene> which likely acts as a substrate check-point during transport; changes to either of these leucine residues have exhibited an increase in transport and a decrease in substrate specificity.<ref name="Manolaridis"/> After the substrate binds Cavity 1 and ATP molecules bind each NBD, the <scene name='83/832932/Atp_bound_cavsleu/5'>leucine plug opens</scene> to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promote substrate release and conversion to the inward-facing conformation.

==Disease==
Dysfunctions in ABCG2 are linked to [https://en.wikipedia.org/wiki/Hyperuricemia hyperuricemia] which can lead to [https://en.wikipedia.org/wiki/Gout gout], [https://en.wikipedia.org/wiki/Kidney_disease kidney disease], and [https://en.wikipedia.org/wiki/Hypertension hypertension], all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 has been found to correlate with a poor prognosis and treatment outcome of certain cancers such as breast, ovarian, and lung.<ref name="Jackson"/>

===Cancer===
ABCG2 hinders cancer treatment by contributing to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance] in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. The inhibition of ABCG2 would stop the transport of anti-cancer drugs out of cancer cells. Due to the potential for ABCG2 inhibition to aid in cancer treatment, efforts have been made to develop specific inhibitors of ABCG2 and other ABC transporters. Some promising inhibitors were derived from fungal toxin [https://en.wikipedia.org/wiki/Fumitremorgin fumitremorgin C]; however, many of those derivatives developed have neurotoxic effects.<ref name="Jackson"/>

===Inhibitors===
ABCG2 <scene name='83/832932/Inhibitor_bound_cavity_1/1'>inhibitors</scene> that bind Cavity 1, acting as competitive inhibitors against ABCG2 substrates. Depending on the size of the inhibitor, one or two molecules can accommodate binding to the cavity and form <scene name='83/832932/Inhibitor_intxns_cavity1/1'>hydrogen bonds, van der Waals, and stacking interactions</scene> within the binding site.<ref name="Jackson"/> Many inhibitors are too big to be transported via the leucine plug resulting in the "clogging" of the transporter. With inhibitors acting as wedges, ABCG2 is locked in the inward-facing conformation and unable to transport molecules out of the cell.<ref name="Manolaridis"/>
</StructureSection>
== References ==
<ref name="Taylor">PMID:28554189</ref>
<ref name="Manolaridis">PMID:30405239</ref>
<ref name="Robey">PMID:29643473</ref>
<ref name="Jackson">PMID:29610494</ref>
<references/>
==Student Contributors==
Julia Pomeroy

Sandbox Reserved 1606

2020-04-16T21:38:31Z

Julia Pomeroy:

{{Sandbox_Reserved_CH462_Biochemistry_II}}
==ABCG2 Multidrug Transporter==

<StructureSection load='5nj3' size='350' side='right' caption='ABCG2 Multidrug Transporter.
Green represents residues in monomer A; Purple represents residues in monomer B. Blue is used to highlight areas of interest in select scenes. (PDB Codes: [https://www.rcsb.org/structure/5NJ3 5NJ3] [https://www.rcsb.org/structure/6HBU 6HBU] [https://www.rcsb.org/structure/6HCO 6HCO] [https://www.rcsb.org/structure/6FFC 6FFC])' scene='83/832932/Overall_structure/2'>

==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 know 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"/> 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"/>

== Structural highlights ==
===Overall Structure===
ABCG2 is a homodimer with each monomer containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/6'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/5'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD binds and processes ATP and is located inside of the cell where it is exposed to the cytosol. The TMD is responsible for binding and transporting any foreign substrates and is embedded in the cell membrane and extends into the extracellular region. (Figure 1). [[Image:membrane domains.png|250 px|right|thumb|Figure 1. Orientation of ABCG2 in relation to the cell membrane. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]

===ATP Bound and Unbound Conformations===
As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity, using the energy of ATP hydrolysis to facilitate transport. After substrate bind in the TMD, one molecule of <scene name='83/832932/Atp_bound_use2/3'>ATP binds each NBD</scene> (2 molecules of ATP total) causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/3'>inward-facing conformation</scene> to an <scene name='83/832932/Outward_facing_conformation/4'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>

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/3'>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"/>

===Cavities and Leucine Plug===
[[Image:Map_leucine_plug.png|250 px|right|thumb|Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The protein is in the inward-facing conformation with Cavity 1 open to the cytosol for substrate recruitment, the Leucine Plug is intact, and Cavity 2 is completely occluded. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]
Substrates are transported through ABCG2 via two cavities separated by a leucine plug (Figure 2). <scene name='83/832932/Cavity_1_zoom_out/2'>Cavity 1</scene> acts as a multidrug binding pocket and is formed by helices at the interface of the monomers in the TMD. When ATP is not bound to the NBDs, Cavity 1 is <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene> in order to recruit substrates for transport. Cavity 1 is <scene name='83/832932/Cavity_1_narrow_surface/4'>narrow</scene> and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules. Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1.<ref name="Taylor"/>

After substrates bind in Cavity 1, ATP binds each NBD leading to the transporter shifting from inward-facing to outward-facing. The outward-facing conformation results in the <scene name='83/832932/Atp_bound_cavity_2/3'>collapse of Cavity 1</scene> in the TMD which closes Cavity 1 to the cytosol and forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.<ref name="Manolaridis"/> <scene name='83/832932/Atp_bound_use_cav_2/2'>Cavity 2</scene>, which is occluded when the protein in is the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.<ref name="Taylor"/> <scene name='83/832932/Atp_bound_use_el_disulfides/3'>Disulfide bonds</scene> in the external loops near the exit of Cavity 2 also help promote substrate release.<ref name="Manolaridis"/> Once Cavity 2 is empty, the protein reverts to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a <scene name='83/832932/Leucine_plug_open_con/7'>leucine plug</scene> which likely acts as a substrate check-point during transport; changes to either of these leucine residues have exhibited an increase in transport and a decrease in substrate specificity.<ref name="Manolaridis"/> After the substrate binds Cavity 1 and ATP molecules bind each NBD, the <scene name='83/832932/Atp_bound_cavsleu/5'>leucine plug opens</scene> to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promote substrate release and conversion to the inward-facing conformation.

==Disease==
Dysfunctions in ABCG2 are linked to [https://en.wikipedia.org/wiki/Hyperuricemia hyperuricemia] which can lead to [https://en.wikipedia.org/wiki/Gout gout], [https://en.wikipedia.org/wiki/Kidney_disease kidney disease], and [https://en.wikipedia.org/wiki/Hypertension hypertension], all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 has been found to correlate with a poor prognosis and treatment outcome of certain cancers such as breast, ovarian, and lung.<ref name="Jackson"/>

===Cancer===
ABCG2 hinders cancer treatment by contributing to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance] in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. The inhibition of ABCG2 would stop the transport of anti-cancer drugs out of cancer cells. Due to the potential for ABCG2 inhibition to aid in cancer treatment, efforts have been made to develop specific inhibitors of ABCG2 and other ABC transporters. Some promising inhibitors were derived from fungal toxin [https://en.wikipedia.org/wiki/Fumitremorgin fumitremorgin C]; however, many of those derivatives developed have neurotoxic effects.<ref name="Jackson"/>

===Inhibitors===
ABCG2 <scene name='83/832932/Inhibitor_bound_cavity_1/1'>inhibitors</scene> that bind Cavity 1, acting as competitive inhibitors against ABCG2 substrates. Depending on the size of the inhibitor, one or two molecules can accommodate binding to the cavity and form <scene name='83/832932/Inhibitor_intxns_cavity1/1'>hydrogen bonds, van der Waals, and stacking interactions</scene> within the binding site.<ref name="Jackson"/> Many inhibitors are too big to be transported via the leucine plug resulting in the "clogging" of the transporter. With inhibitors acting as wedges, ABCG2 is locked in the inward-facing conformation and unable to transport molecules out of the cell.<ref name="Manolaridis"/>
</StructureSection>
== References ==
<ref name="Taylor">PMID:28554189</ref>
<ref name="Manolaridis">PMID:30405239</ref>
<ref name="Robey">PMID:29643473</ref>
<ref name="Jackson">PMID:29610494</ref>
<references/>
==Student Contributors==
Julia Pomeroy

Sandbox Reserved 1606

2020-04-16T21:25:53Z

Julia Pomeroy:

{{Sandbox_Reserved_CH462_Biochemistry_II}}
==ABCG2 Multidrug Transporter==

<StructureSection load='5nj3' size='350' side='right' caption='ABCG2 Multidrug Transporter.
Green represents residues in monomer A; Purple represents residues in monomer B. Blue is used to highlight areas of interest in select scenes. (PDB Codes: [https://www.rcsb.org/structure/5NJ3 5NJ3] [https://www.rcsb.org/structure/6HBU 6HBU] [https://www.rcsb.org/structure/6HCO 6HCO] [https://www.rcsb.org/structure/6FFC 6FFC])' scene='83/832932/Overall_structure/2'>

==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 know 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"/> 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"/>

== Structural highlights ==
===Overall Structure===
ABCG2 is a homodimer with each monomer containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/6'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/5'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD binds and processes ATP and is located inside of the cell where it is exposed to the cytosol. The TMD is responsible for binding and transporting any foreign substrates and is embedded in the cell membrane and extends into the extracellular region. (Figure 1). [[Image:membrane domains.png|250 px|right|thumb|Figure 1. Orientation of ABCG2 in relation to the cell membrane. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]

===ATP Bound and Unbound Conformations===
As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity, using the energy of ATP hydrolysis to facilitate transport. After substrate bind in the TMD, one molecule of <scene name='83/832932/Atp_bound_use2/3'>ATP binds each NBD</scene> (2 molecules of ATP total) causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/3'>inward-facing conformation</scene> to an <scene name='83/832932/Outward_facing_conformation/4'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>

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/3'>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"/>

===Cavities and Leucine Plug===
[[Image:Map_leucine_plug.png|250 px|right|thumb|Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The protein is in the inward-facing conformation with Cavity 1 open to the cytosol for substrate recruitment, the Leucine Plug is intact, and Cavity 2 is completely occluded. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]
Substrates are transported through ABCG2 via two cavities separated by a leucine plug (Figure 2). <scene name='83/832932/Cavity_1_zoom_out/2'>Cavity 1</scene> acts as a multidrug binding pocket and is formed by helices at the interface of the monomers in the TMD. When ATP is not bound to the NBDs, Cavity 1 is <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene> in order to recruit substrates for transport. Cavity 1 is <scene name='83/832932/Cavity_1_narrow_surface/4'>narrow</scene> and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules. Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1.<ref name="Taylor"/>

After substrates bind in Cavity 1, ATP binds each NBD leading to the transporter shifting from inward-facing to outward-facing. The outward-facing conformation results in the <scene name='83/832932/Atp_bound_cavity_2/3'>collapse of Cavity 1</scene> in the TMD which closes Cavity 1 to the cytosol and forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.<ref name="Manolaridis"/> <scene name='83/832932/Atp_bound_use_cav_2/2'>Cavity 2</scene>, which is occluded when the protein in is the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.<ref name="Taylor"/> <scene name='83/832932/Atp_bound_use_el_disulfides/3'>Disulfide bonds</scene> in the external loops near the exit of Cavity 2 also help promote substrate release.<ref name="Manolaridis"/> Once Cavity 2 is empty, the protein reverts to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a <scene name='83/832932/Leucine_plug_open_con/7'>leucine plug</scene> which likely acts as a substrate check-point during transport; changes to either of these leucine residues have exhibited an increase in transport and a decrease in substrate specificity.<ref name="Manolaridis"/> After the substrate binds Cavity 1 and ATP molecules bind each NBD, the <scene name='83/832932/Atp_bound_cavsleu/4'>leucine plug opens</scene> to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promote substrate release and conversion to the inward-facing conformation.

==Disease==
Dysfunctions in ABCG2 are linked to [https://en.wikipedia.org/wiki/Hyperuricemia hyperuricemia] which can lead to [https://en.wikipedia.org/wiki/Gout gout], [https://en.wikipedia.org/wiki/Kidney_disease kidney disease], and [https://en.wikipedia.org/wiki/Hypertension hypertension], all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 has been found to correlate with a poor prognosis and treatment outcome of certain cancers such as breast, ovarian, and lung.<ref name="Jackson"/>

===Cancer===
ABCG2 hinders cancer treatment by contributing to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance] in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. The inhibition of ABCG2 would stop the transport of anti-cancer drugs out of cancer cells. Due to the potential for ABCG2 inhibition to aid in cancer treatment, efforts have been made to develop specific inhibitors of ABCG2 and other ABC transporters. Some promising inhibitors were derived from fungal toxin [https://en.wikipedia.org/wiki/Fumitremorgin fumitremorgin C]; however, many of those derivatives developed have neurotoxic effects.<ref name="Jackson"/>

===Inhibitors===
ABCG2 <scene name='83/832932/Inhibitor_bound_cavity_1/1'>inhibitors</scene> that bind Cavity 1, acting as competitive inhibitors against ABCG2 substrates. Depending on the size of the inhibitor, one or two molecules can accommodate binding to the cavity and form <scene name='83/832932/Inhibitor_intxns_cavity1/1'>hydrogen bonds, van der Waals, and stacking interactions</scene> within the binding site.<ref name="Jackson"/> Many inhibitors are too big to be transported via the leucine plug resulting in the "clogging" of the transporter. With inhibitors acting as wedges, ABCG2 is locked in the inward-facing conformation and unable to transport molecules out of the cell.<ref name="Manolaridis"/>
</StructureSection>
== References ==
<ref name="Taylor">PMID:28554189</ref>
<ref name="Manolaridis">PMID:30405239</ref>
<ref name="Robey">PMID:29643473</ref>
<ref name="Jackson">PMID:29610494</ref>
<references/>
==Student Contributors==
Julia Pomeroy

Sandbox Reserved 1606

2020-04-16T21:21:21Z

Julia Pomeroy:

{{Sandbox_Reserved_CH462_Biochemistry_II}}
==ABCG2 Multidrug Transporter==

<StructureSection load='5nj3' size='350' side='right' caption='ABCG2 Multidrug Transporter.
Green represents residues in monomer A; Purple represents residues in monomer B. Blue is used to highlight areas of interest in select scenes. (PDB Codes: [https://www.rcsb.org/structure/5NJ3 5NJ3] [https://www.rcsb.org/structure/6HBU 6HBU] [https://www.rcsb.org/structure/6HCO 6HCO] [https://www.rcsb.org/structure/6FFC 6FFC])' scene='83/832932/Overall_structure/2'>

==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 know 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"/> 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"/>

== Structural highlights ==
===Overall Structure===
ABCG2 is a homodimer with each monomer containing two domains, the nucleotide binding domain <scene name='83/832932/Overall_structure_nbd_unbound/1'>(NBD)</scene> and the transmembrane domain <scene name='83/832932/Overall_structure_tmd_unbound/2'>(TMD)</scene>, which are fused together as a single peptide chain.<ref name="Taylor"/> The NBD binds and processes ATP and is located inside of the cell where it is exposed to the cytosol. The TMD is responsible for binding and transporting any foreign substrates and is embedded in the cell membrane and extends into the extracellular region. (Figure 1). [[Image:membrane domains.png|250 px|right|thumb|Figure 1. Orientation of ABCG2 in relation to the cell membrane. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]

===ATP Bound and Unbound Conformations===
As an [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC Transporter], ABCG2 exhibits ATPase activity, using the energy of ATP hydrolysis to facilitate transport. After substrate bind in the TMD, one molecule of <scene name='83/832932/Atp_bound_use2/3'>ATP binds each NBD</scene> (2 molecules of ATP total) causing a conformational change of the overall structure from an <scene name='83/832932/Overall_use_2/3'>inward-facing conformation</scene> to an <scene name='83/832932/Outward_facing_conformation/4'>outward-facing conformation</scene>. One molecule of ATP is hydrolyzed to transport substrates across the cell membrane while the second molecule of ATP is hydrolyzed to reset the transporter to its inward-facing conformation.<ref name="Robey"/>

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/3'>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"/>

===Cavities and Leucine Plug===
[[Image:Map_leucine_plug.png|250 px|right|thumb|Figure 2. Locations of Cavities 1 and 2 and the Leucine Plug in ABCG2. The protein is in the inward-facing conformation with Cavity 1 open to the cytosol for substrate recruitment, the Leucine Plug is intact, and Cavity 2 is completely occluded. [https://www.rcsb.org/structure/5NJ3 (5NJ3)]]]
Substrates are transported through ABCG2 via two cavities separated by a leucine plug (Figure 2). <scene name='83/832932/Cavity_1_zoom_out/2'>Cavity 1</scene> acts as a multidrug binding pocket and is formed by helices at the interface of the monomers in the TMD. When ATP is not bound to the NBDs, Cavity 1 is <scene name='83/832932/Overall_structure_cavity_1hel/3'>open to the cytosol</scene> in order to recruit substrates for transport. Cavity 1 is <scene name='83/832932/Cavity_1_narrow_surface/4'>narrow</scene> and full of nonpolar, hydrophobic residues and, as a result, prefers nonpolar, hydrophobic substrates, particularly flat, polycyclic molecules. Substrates, such as estrone sulfate, <scene name='83/832932/Cavity_1_-_use2/4'>form hydrogen bonds and stacking interactions</scene> with residues from each subunit in Cavity 1.<ref name="Taylor"/>

After substrates bind in Cavity 1, ATP binds each NBD leading to the transporter shifting from inward-facing to outward-facing. The outward-facing conformation results in the <scene name='83/832932/Atp_bound_cavity_2/3'>collapse of Cavity 1</scene> in the TMD which closes Cavity 1 to the cytosol and forces the substrate to move forward to Cavity 2 as there is no longer room in Cavity 1 to accommodate substrates.<ref name="Manolaridis"/> <scene name='83/832932/Atp_bound_use_cav_2/2'>Cavity 2</scene>, which is occluded when the protein in is the inward-facing conformation, is now open to the extracellular space and able to release the substrate. Cavity 2 contains a less hydrophobic environment and, as a result, substrates are released due to hydrophobic mismatch.<ref name="Taylor"/> <scene name='83/832932/Atp_bound_use_el_disulfides/3'>Disulfide bonds</scene> in the external loops near the exit of Cavity 2 also help promote substrate release.<ref name="Manolaridis"/> Once Cavity 2 is empty, the protein reverts to the inward-facing conformation via hydrolysis of ATP.

Cavities 1 and 2 are separated by a <scene name='83/832932/Leucine_plug_open_con/7'>leucine plug</scene> which likely acts as a substrate check-point during transport; changes to either of these leucine residues have exhibited an increase in transport and a decrease in substrate specificity.<ref name="Manolaridis"/> After the substrate binds Cavity 1 and ATP molecules bind each NBD, the <scene name='83/832932/Atp_bound_cavsleu/4'>leucine plug opens</scene> to allow the substrate to enter Cavity 2. Once the substrate enters Cavity 2, the plug is able to reform and promote substrate release and conversion to the inward-facing conformation.

==Disease==
Dysfunctions in ABCG2 are linked to [https://en.wikipedia.org/wiki/Hyperuricemia hyperuricemia] which can lead to [https://en.wikipedia.org/wiki/Gout gout], [https://en.wikipedia.org/wiki/Kidney_disease kidney disease], and [https://en.wikipedia.org/wiki/Hypertension hypertension], all of which are thought to be the result of impaired transport of uric acid. Additionally, the expression of ABCG2 has been found to correlate with a poor prognosis and treatment outcome of certain cancers such as breast, ovarian, and lung.<ref name="Jackson"/>

===Cancer===
ABCG2 hinders cancer treatment by contributing to [https://en.wikipedia.org/wiki/Multiple_drug_resistance multidrug resistance] in tumor cells. ABCG2 exports xenbiotics, including vital anti-cancer drugs, which results in the inability to treat cancer cells. The inhibition of ABCG2 would stop the transport of anti-cancer drugs out of cancer cells. Due to the potential for ABCG2 inhibition to aid in cancer treatment, efforts have been made to develop specific inhibitors of ABCG2 and other ABC transporters. Some promising inhibitors were derived from fungal toxin [https://en.wikipedia.org/wiki/Fumitremorgin fumitremorgin C]; however, many of those derivatives developed have neurotoxic effects.<ref name="Jackson"/>

===Inhibitors===
ABCG2 <scene name='83/832932/Inhibitor_bound_cavity_1/1'>inhibitors</scene> that bind Cavity 1, acting as competitive inhibitors against ABCG2 substrates. Depending on the size of the inhibitor, one or two molecules can accommodate binding to the cavity and form <scene name='83/832932/Inhibitor_intxns_cavity1/1'>hydrogen bonds, van der Waals, and stacking interactions</scene> within the binding site.<ref name="Jackson"/> Many inhibitors are too big to be transported via the leucine plug resulting in the "clogging" of the transporter. With inhibitors acting as wedges, ABCG2 is locked in the inward-facing conformation and unable to transport molecules out of the cell.<ref name="Manolaridis"/>
</StructureSection>
== References ==
<ref name="Taylor">PMID:28554189</ref>
<ref name="Manolaridis">PMID:30405239</ref>
<ref name="Robey">PMID:29643473</ref>
<ref name="Jackson">PMID:29610494</ref>
<references/>
==Student Contributors==
Julia Pomeroy

Sandbox Reserved 1606

2020-04-16T21:12:53Z

Julia Pomeroy:

Sandbox Reserved 1606

2020-04-16T21:09:18Z

Julia Pomeroy:

Sandbox Reserved 1606

2020-04-16T20:45:21Z

Julia Pomeroy:

Sandbox Reserved 1606

2020-04-16T20:27:51Z

Julia Pomeroy: