7JK8

EmrE S64V mutant bound to tetra(4-fluorophenyl)phosphonium at pH 5.8

Summary for 7JK8

• Entry DOI: 10.2210/pdb7jk8/pdb
• NMR Information: BMRB: 50411
• Descriptor: Multidrug SMR transporter, tetrakis(4-fluorophenyl)phosphanium (2 entities in total)
• Functional Keywords: small multidrug resistance protein, antiporter, drug efflux pump, membrane protein
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 24362.01

Authors

Shcherbakov, A.A.,Hisao, G.,Mandala, V.S.,Thomas, N.E.,Soltani, M.,Salter, E.A.,Davis Jr., J.H.,Henzler-Wildman, K.A.,Hong, M. (deposition date: 2020-07-27, release date: 2020-12-09, Last modification date: 2024-05-01)

Primary citation

Shcherbakov, A.A.,Hisao, G.,Mandala, V.S.,Thomas, N.E.,Soltani, M.,Salter, E.A.,Davis Jr., J.H.,Henzler-Wildman, K.A.,Hong, M.
Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers.
Nat Commun, 12:172-172, 2021

PubMed Abstract: The dimeric transporter, EmrE, effluxes polyaromatic cationic drugs in a proton-coupled manner to confer multidrug resistance in bacteria. Although the protein is known to adopt an antiparallel asymmetric topology, its high-resolution drug-bound structure is so far unknown, limiting our understanding of the molecular basis of promiscuous transport. Here we report an experimental structure of drug-bound EmrE in phospholipid bilayers, determined using F and H solid-state NMR and a fluorinated substrate, tetra(4-fluorophenyl) phosphonium (F-TPP). The drug-binding site, constrained by 214 protein-substrate distances, is dominated by aromatic residues such as W63 and Y60, but is sufficiently spacious for the tetrahedral drug to reorient at physiological temperature. F-TPP lies closer to the proton-binding residue E14 in subunit A than in subunit B, explaining the asymmetric protonation of the protein. The structure gives insight into the molecular mechanism of multidrug recognition by EmrE and establishes the basis for future design of substrate inhibitors to combat antibiotic resistance.

PubMed: 33420032
DOI: 10.1038/s41467-020-20468-7

Experimental method

SOLID-STATE NMR