7OUL

BDM88832 inhibitor bound to the transmembrane domain of AcrB-R971A

Summary for 7OUL

• Entry DOI: 10.2210/pdb7oul/pdb
• Descriptor: Multidrug efflux pump subunit AcrB, DECYLAMINE-N,N-DIMETHYL-N-OXIDE, TETRADECANE, ... (12 entities in total)
• Functional Keywords: multidrug efflux pump, membrane protein, transport protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 5
• Total formula weight: 386151.67

Authors

Tam, H.K.,Foong, W.E.,Pos, K.M. (deposition date: 2021-06-12, release date: 2021-12-29, Last modification date: 2024-01-31)

Primary citation

Ple, C.,Tam, H.K.,Vieira Da Cruz, A.,Compagne, N.,Jimenez-Castellanos, J.C.,Muller, R.T.,Pradel, E.,Foong, W.E.,Malloci, G.,Ballee, A.,Kirchner, M.A.,Moshfegh, P.,Herledan, A.,Herrmann, A.,Deprez, B.,Willand, N.,Vargiu, A.V.,Pos, K.M.,Flipo, M.,Hartkoorn, R.C.
Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps.
Nat Commun, 13:115-115, 2022

PubMed Abstract: Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.

PubMed: 35013254
DOI: 10.1038/s41467-021-27726-2

Experimental method

X-RAY DIFFRACTION (2.8 Å)