Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae
Autor: | Asha V. Nair, Boyan Bai, Himansha Singh, Hendrik W. van Veen, Keiko Shinoda, Hideaki Fujitani, Sagar Raturi, Satoshi Murakami |
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Přispěvatelé: | Raturi, Sagar [0000-0003-4040-7799], Nair, Asha V. [0000-0002-2037-1138], Murakami, Satoshi [0000-0001-5553-7663], van Veen, Hendrik W. [0000-0002-9658-8077], Apollo - University of Cambridge Repository, Nair, Asha V [0000-0002-2037-1138], van Veen, Hendrik W [0000-0002-9658-8077] |
Rok vydání: | 2021 |
Předmět: |
Organic Cation Transport Proteins
QH301-705.5 education Mutant Medicine (miscellaneous) 96/34 Plasma protein binding Antimicrobial resistance medicine.disease_cause 631/45/173 38/70 Antiporters General Biochemistry Genetics and Molecular Biology 82/80 38/1 03 medical and health sciences 0302 clinical medicine Protein structure Bacterial Proteins medicine Biology (General) Binding site 82/83 Vibrio cholerae 030304 developmental biology Ions 0303 health sciences Binding Sites Chemistry Sodium article Biological Transport Transporter humanities Drug Resistance Multiple Cell biology Transport protein Enzyme mechanisms 631/326/22/1434 behavior and behavior mechanisms Efflux General Agricultural and Biological Sciences 030217 neurology & neurosurgery Hydrogen Protein Binding |
Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-17 (2021) Communications Biology |
ISSN: | 2399-3642 |
Popis: | Funder: Cambridge Commonwealth, European and International Trust (Cambridge Commonwealth, European & International Trust); doi: https://doi.org/10.13039/501100003343 Funder: The Nehru Trust for Cambridge University Funder: H.F. and K.S. were supported in part by the Innovative Drug Discovery Infrastructure through the Functional Control of Biomolecular Systems Priority Issue1 in Post-K Supercomputer Development from MEXT (Project ID: hp190171, hp170255, hp180191, and hp150269. K.S. was also supported in part by JSPS KAKENHI Grant Number JP20H05453. Funder: H.F. and K.S. were supported in part by the Innovative Drug Discovery Infrastructure through the Functional Control of Biomolecular Systems Priority Issue1 in Post-K Supercomputer Development from MEXT (Project ID: hp190171, hp170255, hp180191, and hp150269). Multidrug and toxic compound extrusion (MATE) transport proteins confer multidrug resistance on pathogenic microorganisms and affect pharmacokinetics in mammals. Our understanding of how MATE transporters work, has mostly relied on protein structures and MD simulations. However, the energetics of drug transport has not been studied in detail. Many MATE transporters utilise the electrochemical H+ or Na+ gradient to drive substrate efflux, but NorM-VC from Vibrio cholerae can utilise both forms of metabolic energy. To dissect the localisation and organisation of H+ and Na+ translocation pathways in NorM-VC we engineered chimaeric proteins in which the N-lobe of H+-coupled NorM-PS from Pseudomonas stutzeri is fused to the C-lobe of NorM-VC, and vice versa. Our findings in drug binding and transport experiments with chimaeric, mutant and wildtype transporters highlight the versatile nature of energy coupling in NorM-VC, which enables adaptation to fluctuating salinity levels in the natural habitat of V. cholerae. |
Databáze: | OpenAIRE |
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