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| | ==Structure of an inhibitor-bound ABC transporter== | | ==Structure of an inhibitor-bound ABC transporter== |
| - | <StructureSection load='6ffc' size='340' side='right'caption='[[6ffc]], [[Resolution|resolution]] 3.56Å' scene=''> | + | <SX load='6ffc' size='340' side='right' viewer='molstar' caption='[[6ffc]], [[Resolution|resolution]] 3.56Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ffc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FFC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ffc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FFC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BWQ:~{tert}-butyl+3-[(2~{S},5~{S},8~{S})-14-cyclopentyloxy-2-(2-methylpropyl)-4,7-bis(oxidanylidene)-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraen-5-yl]propanoate'>BWQ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.56Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ABCG2, ABCP, BCRP, BCRP1, MXR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BWQ:~{tert}-butyl+3-[(2~{S},5~{S},8~{S})-14-cyclopentyloxy-2-(2-methylpropyl)-4,7-bis(oxidanylidene)-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraen-5-yl]propanoate'>BWQ</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ffc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffc OCA], [http://pdbe.org/6ffc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ffc RCSB], [http://www.ebi.ac.uk/pdbsum/6ffc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffc ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ffc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffc OCA], [https://pdbe.org/6ffc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ffc RCSB], [https://www.ebi.ac.uk/pdbsum/6ffc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffc ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ABCG2_HUMAN ABCG2_HUMAN]] High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.<ref>PMID:12958161</ref> <ref>PMID:20705604</ref> <ref>PMID:22132962</ref> <ref>PMID:23189181</ref> | + | [https://www.uniprot.org/uniprot/ABCG2_HUMAN ABCG2_HUMAN] High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.<ref>PMID:12958161</ref> <ref>PMID:20705604</ref> <ref>PMID:22132962</ref> <ref>PMID:23189181</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6ffc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6ffc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[ABC transporter 3D structures|ABC transporter 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Altmann, K H]] | + | [[Category: Altmann KH]] |
| - | [[Category: Bartholomaeus, R]] | + | [[Category: Bartholomaeus R]] |
| - | [[Category: Bauer, S]] | + | [[Category: Bauer S]] |
| - | [[Category: Bause, M]] | + | [[Category: Bause M]] |
| - | [[Category: Bernhardt, G]] | + | [[Category: Bernhardt G]] |
| - | [[Category: Buschauer, A]] | + | [[Category: Buschauer A]] |
| - | [[Category: Jackson, S M]] | + | [[Category: Jackson SM]] |
| - | [[Category: Koenig, B]] | + | [[Category: Koenig B]] |
| - | [[Category: Kowal, J]] | + | [[Category: Kowal J]] |
| - | [[Category: Locher, K P]] | + | [[Category: Locher KP]] |
| - | [[Category: Manolaridis, I]] | + | [[Category: Manolaridis I]] |
| - | [[Category: Stahlberg, H]] | + | [[Category: Stahlberg H]] |
| - | [[Category: Taylor, N M.I]] | + | [[Category: Taylor NMI]] |
| - | [[Category: Zechner, M]] | + | [[Category: Zechner M]] |
| - | [[Category: Abc transporter]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
ABCG2_HUMAN High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.[1] [2] [3] [4]
Publication Abstract from PubMed
ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators.
Structural basis of small-molecule inhibition of human multidrug transporter ABCG2.,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 Nat Struct Mol Biol. 2018 Apr;25(4):333-340. doi: 10.1038/s41594-018-0049-1. Epub, 2018 Apr 2. PMID:29610494[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB. The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J. 2003 Nov;17(14):2085-7. Epub 2003 Sep 4. PMID:12958161 doi:http://dx.doi.org/10.1096/fj.02-1131fje
- ↑ Desuzinges-Mandon E, Arnaud O, Martinez L, Huche F, Di Pietro A, Falson P. ABCG2 transports and transfers heme to albumin through its large extracellular loop. J Biol Chem. 2010 Oct 22;285(43):33123-33. doi: 10.1074/jbc.M110.139170. Epub, 2010 Aug 12. PMID:20705604 doi:http://dx.doi.org/10.1074/jbc.M110.139170
- ↑ Nakayama A, Matsuo H, Takada T, Ichida K, Nakamura T, Ikebuchi Y, Ito K, Hosoya T, Kanai Y, Suzuki H, Shinomiya N. ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1091-7. doi:, 10.1080/15257770.2011.633953. PMID:22132962 doi:http://dx.doi.org/10.1080/15257770.2011.633953
- ↑ Kobuchi H, Moriya K, Ogino T, Fujita H, Inoue K, Shuin T, Yasuda T, Utsumi K, Utsumi T. Mitochondrial localization of ABC transporter ABCG2 and its function in 5-aminolevulinic acid-mediated protoporphyrin IX accumulation. PLoS One. 2012;7(11):e50082. doi: 10.1371/journal.pone.0050082. Epub 2012 Nov 26. PMID:23189181 doi:http://dx.doi.org/10.1371/journal.pone.0050082
- ↑ 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:http://dx.doi.org/10.1038/s41594-018-0049-1
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