Broadly conserved Na + -binding site in the N-lobe of prokaryotic multidrug MATE transporters
| Autor: | Emel Ficici, Wenchang Zhou, José D. Faraldo-Gómez, Steven Castellano |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Multidisciplinary biology Chemistry Cell Crystallographic data Transporter biology.organism_classification Transmembrane protein 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Membrane protein Biochemistry medicine Pyrococcus furiosus Na binding Efflux 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences. 115 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1802080115 |
| Popis: | Multidrug and toxic-compound extrusion (MATE) proteins comprise an important but largely uncharacterized family of secondary-active transporters. In both eukaryotes and prokaryotes, these transporters protect the cell by catalyzing the efflux of a broad range of cytotoxic compounds, including human-made antibiotics and anticancer drugs. MATEs are thus potential pharmacological targets against drug-resistant pathogenic bacteria and tumor cells. The activity of MATEs is powered by transmembrane electrochemical ion gradients, but their molecular mechanism and ion specificity are not understood, in part because high-quality structural information is limited. Here, we use computational methods to study PfMATE, from Pyrococcus furiosus, whose structure is the best resolved to date. Analysis of available crystallographic data and additional molecular dynamics simulations unequivocally reveal an occupied Na+-binding site in the N-lobe of this transporter, which had not been previously recognized. We find this site to be selective against K+ and broadly conserved among prokaryotic MATEs, including homologs known to be Na+-dependent such as NorM-VC, VmrA, and ClbM, for which the location of the Na+ site had been debated. We note, however, that the chemical makeup of the proposed Na+ site indicates it is weakly specific against H+, explaining why MATEs featuring this Na+-binding motif may be solely driven by H+ in laboratory conditions. We further posit that the concurrent coupling to H+ and Na+ gradients observed for some Na+-driven MATEs owes to a second H+-binding site, within the C-lobe. In summary, our study provides insights into the structural basis for the complex ion dependency of MATE transporters. |
| Databáze: | OpenAIRE |
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