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==Cryo-EM structure of the human ABCG2-MZ29-Fab complex with cholesterol and PE lipids docked== | ==Cryo-EM structure of the human ABCG2-MZ29-Fab complex with cholesterol and PE lipids docked== | ||
<StructureSection load='6hij' size='340' side='right' caption='[[6hij]], [[Resolution|resolution]] 3.56Å' scene=''> | <StructureSection load='6hij' size='340' side='right'caption='[[6hij]], [[Resolution|resolution]] 3.56Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6hij]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HIJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HIJ FirstGlance]. <br> | <table><tr><td colspan='2'>[[6hij]] 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=6HIJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HIJ 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>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PEE:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEE</scene></td></tr> | </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>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PEE:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEE</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ffc|6ffc]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ffc|6ffc]]</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='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=6hij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hij OCA], [http://pdbe.org/6hij PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hij RCSB], [http://www.ebi.ac.uk/pdbsum/6hij PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hij ProSAT]</span></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=6hij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hij OCA], [http://pdbe.org/6hij PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hij RCSB], [http://www.ebi.ac.uk/pdbsum/6hij PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hij 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> | [[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> | ||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:29610494</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6hij" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Altmann, K H]] | [[Category: Altmann, K H]] | ||
[[Category: Bartholomaeus, R]] | [[Category: Bartholomaeus, R]] | ||
Revision as of 11:16, 3 April 2019
Cryo-EM structure of the human ABCG2-MZ29-Fab complex with cholesterol and PE lipids dockedCryo-EM structure of the human ABCG2-MZ29-Fab complex with cholesterol and PE lipids docked
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 PubMedABCG2 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. References
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