4dx5: Difference between revisions
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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== | |||
<StructureSection load='4dx5' size='340' side='right' caption='[[4dx5]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dx5]] 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=4DX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DX5 FirstGlance]. <br> | |||
==Function== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C14:TETRADECANE'>C14</scene>, <scene name='pdbligand=D10:DECANE'>D10</scene>, <scene name='pdbligand=D12:DODECANE'>D12</scene>, <scene name='pdbligand=DD9:NONANE'>DD9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEX:HEXANE'>HEX</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=LMU:DODECYL-ALPHA-D-MALTOSIDE'>LMU</scene>, <scene name='pdbligand=MIY:(4S,4AS,5AR,12AS)-4,7-BIS(DIMETHYLAMINO)-3,10,12,12A-TETRAHYDROXY-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDROTETRACENE-2-CARBOXAMIDE'>MIY</scene>, <scene name='pdbligand=OCT:N-OCTANE'>OCT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UND:UNDECANE'>UND</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dx6|4dx6]], [[4dx7|4dx7]]</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])</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=4dx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dx5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dx5 RCSB], [http://www.ebi.ac.uk/pdbsum/4dx5 PDBsum]</span></td></tr> | |||
</table> | |||
== 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> | [[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> | ||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:22451937</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Ecoli]] | [[Category: Ecoli]] | ||
[[Category: Bohnert, J A | [[Category: Synthetic construct sequences]] | ||
[[Category: Brandstaetter, L | [[Category: Bohnert, J A]] | ||
[[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, M G]] | ||
[[Category: Pos, K M | [[Category: Kern, W V]] | ||
[[Category: Seeger, M A | [[Category: Pos, K M]] | ||
[[Category: Verrey, F | [[Category: Seeger, M A]] | ||
[[Category: Verrey, F]] | |||
[[Category: Darpin]] | [[Category: Darpin]] | ||
[[Category: Membrane protein]] | [[Category: Membrane protein]] | ||
[[Category: Multidrug efflux protein]] | [[Category: Multidrug efflux protein]] | ||
[[Category: Transport protein]] | [[Category: Transport protein]] | ||
Revision as of 07:09, 25 December 2014
Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loopTransport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop
Structural highlights
Function[ACRB_ECOLI] AcrAB is a drug efflux protein with a broad substrate specificity.[1] [2] [3] Publication Abstract from PubMedAcrAB-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
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