7a6f: Difference between revisions
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==Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and zosuquidar== | |||
<StructureSection load='7a6f' size='340' side='right'caption='[[7a6f]], [[Resolution|resolution]] 3.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7a6f]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A6F FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene></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=7a6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a6f OCA], [https://pdbe.org/7a6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a6f RCSB], [https://www.ebi.ac.uk/pdbsum/7a6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a6f ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/MDR1_HUMAN MDR1_HUMAN] Ulcerative colitis. Disease susceptibility is associated with variations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MDR1_HUMAN MDR1_HUMAN] Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors. | |||
Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.,Nosol K, Romane K, Irobalieva RN, Alam A, Kowal J, Fujita N, Locher KP Proc Natl Acad Sci U S A. 2020 Oct 5. pii: 2010264117. doi:, 10.1073/pnas.2010264117. PMID:33020312<ref>PMID:33020312</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7a6f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[ABC transporter 3D structures|ABC transporter 3D structures]] | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Locher KP]] | |||
[[Category: Nosol K]] | |||
Latest revision as of 09:02, 21 November 2024
Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and zosuquidarNanodisc reconstituted human ABCB1 in complex with MRK16 Fab and zosuquidar
Structural highlights
DiseaseMDR1_HUMAN Ulcerative colitis. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionMDR1_HUMAN Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Publication Abstract from PubMedABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors. Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.,Nosol K, Romane K, Irobalieva RN, Alam A, Kowal J, Fujita N, Locher KP Proc Natl Acad Sci U S A. 2020 Oct 5. pii: 2010264117. doi:, 10.1073/pnas.2010264117. PMID:33020312[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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