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==CryoEM structure of the ABC transporter BmrA E504A mutant in complex with ATP-Mg== | ==CryoEM structure of the ABC transporter BmrA E504A mutant in complex with ATP-Mg== | ||
<StructureSection load='7ow8' size='340' side='right'caption='[[7ow8]]' scene=''> | <StructureSection load='7ow8' size='340' side='right'caption='[[7ow8]], [[Resolution|resolution]] 3.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OW8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OW8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ow8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OW8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OW8 FirstGlance]. <br> | ||
</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=7ow8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ow8 OCA], [https://pdbe.org/7ow8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ow8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ow8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ow8 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7ow8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ow8 OCA], [https://pdbe.org/7ow8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ow8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ow8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ow8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/BMRA_BACSU BMRA_BACSU]] An efflux transporter able to transport Hoechst 33342, ethidium bromide, doxorubicin and a number of other drugs in vitro into inside out vesicles. The endogenous substrate is unknown. It has been suggested that NBD dimerization induced by ATP-binding causes a large conformational change responsible for substrate translocation (PubMed:18215075). Transmembrane domains (TMD) form a pore in the inner membrane and the ATP-binding domain (NBD) is responsible for energy generation (Probable).<ref>PMID:18215075</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg(2+)-bound outward-facing conformations of the Bacillus subtilis (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in B. subtilis. Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5'-6' of the other. They induce a rearrangement of TM1-2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open. | |||
Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter.,Chaptal V, Zampieri V, Wiseman B, Orelle C, Martin J, Nguyen KA, Gobet A, Di Cesare M, Magnard S, Javed W, Eid J, Kilburg A, Peuchmaur M, Marcoux J, Monticelli L, Hogbom M, Schoehn G, Jault JM, Boumendjel A, Falson P Sci Adv. 2022 Jan 28;8(4):eabg9215. doi: 10.1126/sciadv.abg9215. Epub 2022 Jan, 26. PMID:35080979<ref>PMID:35080979</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ow8" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chaptal V]] | [[Category: Chaptal, V]] | ||
[[Category: Falson P]] | [[Category: Falson, P]] | ||
[[Category: Gobet A]] | [[Category: Gobet, A]] | ||
[[Category: Schoehn G]] | [[Category: Schoehn, G]] | ||
[[Category: Bmra abc transporter complex with atp-mg multidrug resistance]] | |||
[[Category: Transport protein]] | |||
Revision as of 10:14, 2 February 2022
CryoEM structure of the ABC transporter BmrA E504A mutant in complex with ATP-MgCryoEM structure of the ABC transporter BmrA E504A mutant in complex with ATP-Mg
Structural highlights
Function[BMRA_BACSU] An efflux transporter able to transport Hoechst 33342, ethidium bromide, doxorubicin and a number of other drugs in vitro into inside out vesicles. The endogenous substrate is unknown. It has been suggested that NBD dimerization induced by ATP-binding causes a large conformational change responsible for substrate translocation (PubMed:18215075). Transmembrane domains (TMD) form a pore in the inner membrane and the ATP-binding domain (NBD) is responsible for energy generation (Probable).[1] Publication Abstract from PubMedMultidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg(2+)-bound outward-facing conformations of the Bacillus subtilis (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in B. subtilis. Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5'-6' of the other. They induce a rearrangement of TM1-2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open. Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter.,Chaptal V, Zampieri V, Wiseman B, Orelle C, Martin J, Nguyen KA, Gobet A, Di Cesare M, Magnard S, Javed W, Eid J, Kilburg A, Peuchmaur M, Marcoux J, Monticelli L, Hogbom M, Schoehn G, Jault JM, Boumendjel A, Falson P Sci Adv. 2022 Jan 28;8(4):eabg9215. doi: 10.1126/sciadv.abg9215. Epub 2022 Jan, 26. PMID:35080979[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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