Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity.

Autor:	Lazarova M; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Eicher T; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Börnsen C; Buchmann Institute for Molecular Life Sciences and Institute of Biophysics, Goethe-University Frankfurt, Germany., Zeng H; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Athar M; Department of Physics, University of Cagliari, Italy., Okada U; Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan., Yamashita E; Institute for Protein Research, Osaka University, Japan., Spannaus IM; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Borgosch M; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Cha HJ; Institute of Biochemistry, Goethe-University Frankfurt, Germany., Vargiu AV; Department of Physics, University of Cagliari, Italy., Murakami S; Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan., Diederichs K; Department of Biology, University of Konstanz, Germany., Frangakis AS; Buchmann Institute for Molecular Life Sciences and Institute of Biophysics, Goethe-University Frankfurt, Germany., Pos KM; Institute of Biochemistry, Goethe-University Frankfurt, Germany.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI:	10.1101/2024.11.22.624703
Abstrakt:	Antibiotic efflux plays a key role for the multidrug resistance in Gram-negative bacteria 1-3 . Multidrug efflux pumps of the resistance nodulation and cell division (RND) superfamily function as part of cell envelope spanning systems and provide resistance to diverse antibiotics 4,5 . Here, we identify two phylogenetic clusters of RND proteins with conserved binding pocket residues. Based on the characterisation of one representative of each cluster, K. pneumoniae OqxB and E. coli AcrB, we show that the transfer of a single conserved residue between both clusters alters the resistance against a panel of structurally unrelated drugs. The substitution is not only associated with changes in the binding pocket architecture, but also alters the equilibrium between the conformational states of the transport cycle. We show that AcrB and OqxB adopt fundamentally different apo states that suggest different mechanisms of initial substrate binding and might determine the differences between the substrate preferences of both pumps. The observed conformational heterogeneity between different RND clusters is suggested to be phylogenetically conserved and might play a role for the diversification of the resistance phenotype between homologous RND multidrug efflux pumps. Competing Interests: Competing interests: The authors declare no competing interests.
Databáze:	MEDLINE
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