Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment
| Autor: | Pin-Chia Hsu, Gisela Storz, Ben F. Luisi, Mona W. Orr, Syma Khalid, Firdaus Samsudin, Leana M. Ramos, Catherine E. Newman, Arthur Neuberger, Andrzej Szewczak-Harris, Dijun Du, Mekdes Debela |
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| Přispěvatelé: | Luisi, Ben [0000-0003-1144-9877], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular transmembrane transport Protein Conformation medicine.disease_cause Crystallography X-Ray 01 natural sciences Substrate Specificity chemistry.chemical_compound Structural Biology antibiotic Cardiolipin 0303 health sciences allostery 010304 chemical physics biology Escherichia coli Proteins 030302 biochemistry & molecular biology Transmembrane protein drug efflux cryoEM Efflux small protein Multidrug Resistance-Associated Proteins Protein Binding Cardiolipins Allosteric regulation Binding pocket Article 03 medical and health sciences Allosteric Regulation 0103 physical sciences Drug Resistance Bacterial medicine Escherichia coli Molecular Biology 030304 developmental biology structural model Binding Sites Cryoelectron Microscopy Transporter Membrane transport biology.organism_classification molecular dynamics Chloramphenicol Membrane protein chemistry Multiprotein Complexes Biophysics Carrier Proteins Bacteria |
| Zdroj: | Structure Structure(London, England:1993) |
| Popis: | Summary The small protein AcrZ in Escherichia coli interacts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins. Graphical Abstract Highlights • Structure of an RND transporter with an allosteric modulator in a membrane environment • Cooperation of lipid and small protein in allosterically modulating transport activity Multidrug efflux in bacteria contributes to their antibiotic resistance during host infection and is driven by transporters in the bacterial cell envelope. In this study, the structure of a multidrug transporter was determined in an environment mimicking the natural membrane, which includes a small protein that modulates efflux activity. |
| Databáze: | OpenAIRE |
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