A model for allosteric communication in drug transport by the AcrAB-TolC tripartite efflux pump
| cam.depositDate | 2022-01-13 | |
| cam.issuedOnline | 2022-01-01 | |
| cam.orpheus.success | 2022-01-13 - Embargo set during processing via Fast-track | |
| dc.contributor.author | Luisi, Bonaventura | |
| dc.contributor.orcid | Luisi, Ben [0000-0003-1144-9877] | |
| dc.date.accessioned | 2022-01-14T00:31:38Z | |
| dc.date.available | 2022-01-14T00:31:38Z | |
| dc.date.updated | 2022-01-13T12:51:05Z | |
| dc.description.abstract | RND family efflux pumps are complex macromolecular machines involved in multidrug re-sistance by extruding antibiotics from the cell. While structural studies and molecular dynamics simulations have provided insights into the architecture and conformational states of the pumps, the path followed by conformational changes from the inner membrane protein (IMP) to the periplasmic membrane fusion protein (MFP) and to the outer membrane protein (OMP) is not fully understood. Here, we investigate AcrAB-TolC efflux pump’s allostery, by comparing resting and transport states using difference distance matrices supplemented with evolutionary couplings data and buried surface area measurements. Our analysis indicates that substrate binding by the IMP triggers quaternary level conformational changes in the MFP, which trigger OMP to switch from the closed state to the open state, accompanied by a considerable increase in the interface area between the MFP subunits and between the OMPs and MFPs. This suggests that the pump’s transport-ready state is at a more favourable energy level than the resting state, but raises the puzzle of how the pump does not become stably trapped in a transport-intermediate state. We propose a model for pump allostery that includes a downhill energetic transition process from a proposed ‘activated’ transport state back to the resting pump. | |
| dc.description.sponsorship | ERC | |
| dc.identifier.doi | 10.17863/CAM.80150 | |
| dc.identifier.issn | 2079-6382 | |
| dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/332706 | |
| dc.language.iso | eng | |
| dc.publisher | MDPI AG | |
| dc.publisher.department | Department of Biochemistry | |
| dc.rights | Attribution 4.0 International | |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
| dc.title | A model for allosteric communication in drug transport by the AcrAB-TolC tripartite efflux pump | |
| dc.type | Article | |
| dcterms.dateAccepted | 2022-01-01 | |
| prism.publicationName | Antibiotics | |
| pubs.funder-project-id | European Research Council (742210) | |
| pubs.licence-display-name | Apollo Repository Deposit Licence Agreement | |
| pubs.licence-identifier | apollo-deposit-licence-2-1 | |
| rioxxterms.type | Journal Article/Review | |
| rioxxterms.version | AM |
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