Dynamics underlie the drug recognition mechanism by the efflux transporter EmrE.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 May 2024
28 May 2024
Historique:
received:
12
12
2023
accepted:
14
05
2024
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
28
5
2024
Statut:
epublish
Résumé
The multidrug efflux transporter EmrE from Escherichia coli requires anionic residues in the substrate binding pocket for coupling drug transport with the proton motive force. Here, we show how protonation of a single membrane embedded glutamate residue (Glu14) within the homodimer of EmrE modulates the structure and dynamics in an allosteric manner using NMR spectroscopy. The structure of EmrE in the Glu14 protonated state displays a partially occluded conformation that is inaccessible for drug binding by the presence of aromatic residues in the binding pocket. Deprotonation of a single Glu14 residue in one monomer induces an equilibrium shift toward the open state by altering its side chain position and that of a nearby tryptophan residue. This structural change promotes an open conformation that facilitates drug binding through a conformational selection mechanism and increases the binding affinity by approximately 2000-fold. The prevalence of proton-coupled exchange in efflux systems suggests a mechanism that may be shared in other antiporters where acid/base chemistry modulates access of drugs to the substrate binding pocket.
Identifiants
pubmed: 38806470
doi: 10.1038/s41467-024-48803-2
pii: 10.1038/s41467-024-48803-2
doi:
Substances chimiques
EmrE protein, E coli
147995-06-0
Escherichia coli Proteins
0
Antiporters
0
Protons
0
Glutamic Acid
3KX376GY7L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4537Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : R01AI108889
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : R01AI165782
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R35GM127040
Informations de copyright
© 2024. The Author(s).
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