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| | ==Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop== | | ==Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop== |
| - | <StructureSection load='4dx6' size='340' side='right' caption='[[4dx6]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4dx6' size='340' side='right'caption='[[4dx6]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dx6]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DX6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DX6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dx6]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DX6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DX6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dx5|4dx5]], [[4dx7|4dx7]]</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=4dx6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dx6 OCA], [https://pdbe.org/4dx6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dx6 RCSB], [https://www.ebi.ac.uk/pdbsum/4dx6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dx6 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">acrB, acrE, b0462, JW0451 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI]), artificial gene ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=32630 SYNTHETIC CONSTRUCT sequences])</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=4dx6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dx6 OCA], [http://pdbe.org/4dx6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dx6 RCSB], [http://www.ebi.ac.uk/pdbsum/4dx6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dx6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACRB_ECOLI ACRB_ECOLI]] AcrAB is a drug efflux protein with a broad substrate specificity.<ref>PMID:16915237</ref> <ref>PMID:16946072</ref> <ref>PMID:17194213</ref> | + | [[https://www.uniprot.org/uniprot/ACRB_ECOLI ACRB_ECOLI]] AcrAB is a drug efflux protein with a broad substrate specificity.<ref>PMID:16915237</ref> <ref>PMID:16946072</ref> <ref>PMID:17194213</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ecoli]] | + | [[Category: Escherichia coli K-12]] |
| - | [[Category: Synthetic construct sequences]] | + | [[Category: Large Structures]] |
| - | [[Category: Bohnert, J A]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Brandstaetter, L]] | + | [[Category: Bohnert JA]] |
| - | [[Category: Cha, H]] | + | [[Category: Brandstaetter L]] |
| - | [[Category: Diederichs, K]] | + | [[Category: Cha H]] |
| - | [[Category: Eicher, T]] | + | [[Category: Diederichs K]] |
| - | [[Category: El-Delik, J]] | + | [[Category: Eicher T]] |
| - | [[Category: Gruetter, M G]] | + | [[Category: El-Delik J]] |
| - | [[Category: Kern, W V]] | + | [[Category: Gruetter MG]] |
| - | [[Category: Pos, K M]] | + | [[Category: Kern WV]] |
| - | [[Category: Seeger, M A]] | + | [[Category: Pos KM]] |
| - | [[Category: Verrey, F]] | + | [[Category: Seeger MA]] |
| - | [[Category: Darpin]]
| + | [[Category: Verrey F]] |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Multidrug efflux protein]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
[ACRB_ECOLI] AcrAB is a drug efflux protein with a broad substrate specificity.[1] [2] [3]
Publication Abstract from PubMed
AcrAB-TolC is the major efflux protein complex in Escherichia coli extruding a vast variety of antimicrobial agents from the cell. The inner membrane component AcrB is a homotrimer, and it has been postulated that the monomers cycle consecutively through three conformational stages designated loose (L), tight (T), and open (O) in a concerted fashion. Binding of drugs has been shown at a periplasmic deep binding pocket in the T conformation. The initial drug-binding step and transport toward this drug-binding site has been elusive thus far. Here we report high resolution structures (1.9-2.25 A) of AcrB/designed ankyrin repeat protein (DARPin) complexes with bound minocycline or doxorubicin. In the AcrB/doxorubicin cocrystal structure, binding of three doxorubicin molecules is apparent, with one doxorubicin molecule bound in the deep binding pocket of the T monomer and two doxorubicin molecules in a stacked sandwich arrangement in an access pocket at the lateral periplasmic cleft of the L monomer. This access pocket is separated from the deep binding pocket apparent in the T monomer by a switch-loop. The localization and conformational flexibility of this loop seems to be important for large substrates, because a G616N AcrB variant deficient in macrolide transport exhibits an altered conformation within this loop region. Transport seems to be a stepwise process of initial drug uptake in the access pocket of the L monomer and subsequent accommodation of the drug in the deep binding pocket during the L to T transition to the internal deep binding pocket of the T monomer.
Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop.,Eicher T, Cha HJ, Seeger MA, Brandstatter L, El-Delik J, Bohnert JA, Kern WV, Verrey F, Grutter MG, Diederichs K, Pos KM Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5687-92. Epub 2012 Mar 26. PMID:22451937[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature. 2006 Sep 14;443(7108):173-9. Epub 2006 Aug 16. PMID:16915237 doi:10.1038/nature05076
- ↑ Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science. 2006 Sep 1;313(5791):1295-8. PMID:16946072 doi:313/5791/1295
- ↑ Sennhauser G, Amstutz P, Briand C, Storchenegger O, Grutter MG. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol. 2007 Jan;5(1):e7. PMID:17194213 doi:10.1371/journal.pbio.0050007
- ↑ Eicher T, Cha HJ, Seeger MA, Brandstatter L, El-Delik J, Bohnert JA, Kern WV, Verrey F, Grutter MG, Diederichs K, Pos KM. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5687-92. Epub 2012 Mar 26. PMID:22451937 doi:10.1073/pnas.1114944109
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