Sandbox Reserved 1613: Difference between revisions
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==General Structure== | ==General Structure== | ||
The ABCG2 protein is comprised of a homodimer which each have two specific domains: one spanning the cell membrane and one involved with nucleotide binding. | The ABCG2 protein is comprised of a homodimer which each have two specific domains: one spanning the cell membrane and one involved with nucleotide binding. | ||
=== Structural highlights === | |||
[[Image:Ligand_Interactions_6ffc.png|400 px|right|thumb|Figure 2]] | |||
Multidrug Transporter ABCG2 is a <scene name='83/832937/Dimer/1'>dimer</scene> that consists of two cavities seperated 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> (red is inter- and intra-molecular disulfides, purple is intra-molecular only) promote the release of the substrate from the cavity into the extracellular space. | |||
<ref name=”Jackson”>PMID:29610494</ref> | |||
<ref name="Manolaridis">PMID:30405239</ref> | |||
===Transmembrane Domains=== | ===Transmembrane Domains=== | ||
In the transmembrane domain is located the leucine plug that separates the first site of binding from the second site of binding for the substrate. This is only opened when the protein is shifted from its interior facing to exterior facing formation by the transfer of a phosphate off of an ATP. This causes a shift and transfer to the second binding site which is open to the extracellular matrix. The Fab-5D3 antigen binding fragment was found to stabilize the protein in its inward facing conformation which allowed for high resolution images of the protein to be taken in this conformation. Without Fab attached, the conformation of the protein was constantly in flux, transporting substrates out of the cell constantly. Fab was found to only stabilize ABCG2 on the extracellular side. Three important interactions between Fab fragments and ABCG2 were important to binding stability and favorability. This binding occurred at the <scene name='83/832939/El-3/1'>EL-3</scene> of ABCG2 which is the helices that stretches the furthest from the cell membrane. These interactions were two disulfide bonds, one intramolecularly and the other intermolecularly, and an n-<scene name='83/832939/Glycos_site/1'>glycosylation site</scene> at residue Asn-596. | In the transmembrane domain is located the leucine plug that separates the first site of binding from the second site of binding for the substrate. This is only opened when the protein is shifted from its interior facing to exterior facing formation by the transfer of a phosphate off of an ATP. This causes a shift and transfer to the second binding site which is open to the extracellular matrix. The Fab-5D3 antigen binding fragment was found to stabilize the protein in its inward facing conformation which allowed for high resolution images of the protein to be taken in this conformation. Without Fab attached, the conformation of the protein was constantly in flux, transporting substrates out of the cell constantly. Fab was found to only stabilize ABCG2 on the extracellular side. Three important interactions between Fab fragments and ABCG2 were important to binding stability and favorability. This binding occurred at the <scene name='83/832939/El-3/1'>EL-3</scene> of ABCG2 which is the helices that stretches the furthest from the cell membrane. These interactions were two disulfide bonds, one intramolecularly and the other intermolecularly, and an n-<scene name='83/832939/Glycos_site/1'>glycosylation site</scene> at residue Asn-596. | ||
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One of the causes for multidrug resistant cancers is the excretion of cancer drugs out of the cell, thereby decreasing the effective intracellular concentration. ABCG2, also known as the breast cancer resistance protein (BCRP), effluxes multiple chemotherapeutic agents such as [https://en.wikipedia.org/wiki/Mitoxantrone mitoxantrone] and [https://en.wikipedia.org/wiki/Camptothecin camptothecin] analogies, making the cancerous breast cells resistant to chemotherapy. Competitive inhibitors, such as <scene name='83/832939/Abcg2_bound_to_mz29/3'>MZ29</scene>, that shut down ABCG2 to stop the efflux of cancer drugs in order to combat the resistivity of breast cancer. <ref>[ https://en.wikipedia.org/wiki/ABCG2 "ABCG2 -." Wikipedia, the Free Encyclopedia. Web. 20 Apr. 2020].</ref><ref name=”Jackson”>PMID:29610494</ref> | One of the causes for multidrug resistant cancers is the excretion of cancer drugs out of the cell, thereby decreasing the effective intracellular concentration. ABCG2, also known as the breast cancer resistance protein (BCRP), effluxes multiple chemotherapeutic agents such as [https://en.wikipedia.org/wiki/Mitoxantrone mitoxantrone] and [https://en.wikipedia.org/wiki/Camptothecin camptothecin] analogies, making the cancerous breast cells resistant to chemotherapy. Competitive inhibitors, such as <scene name='83/832939/Abcg2_bound_to_mz29/3'>MZ29</scene>, that shut down ABCG2 to stop the efflux of cancer drugs in order to combat the resistivity of breast cancer. <ref>[ https://en.wikipedia.org/wiki/ABCG2 "ABCG2 -." Wikipedia, the Free Encyclopedia. Web. 20 Apr. 2020].</ref><ref name=”Jackson”>PMID:29610494</ref> | ||
</StructureSection> | </StructureSection> | ||
