3W9H

Structural basis for the inhibition of bacterial multidrug exporters

Summary for 3W9H

• Entry DOI: 10.2210/pdb3w9h/pdb
• Related: 3W9I 3W9J
• Descriptor: Acriflavine resistance protein B, [{2-[({[(3R)-1-{8-[(4-tert-butyl-1,3-thiazol-2-yl)carbamoyl]-4-oxo-3-[(E)-2-(1H-tetrazol-5-yl)ethenyl]-4H-pyrido[1,2-a]pyrimidin-2-yl}piperidin-3-yl]oxy}carbonyl)amino]ethyl}(dimethyl)ammonio]acetate (3 entities in total)
• Functional Keywords: acrb, efflux pump, transporter, multidrug efflux pump, acra, tolc, inner membrane, transport protein, membrane protein
• Biological source: Escherichia coli
• Cellular location: Cell inner membrane ; Multi- pass membrane protein : P31224
• Total number of polymer chains: 3
• Total formula weight: 335902.32

Authors

Sakurai, K.,Nagata, C.,Nakashima, R.,Yamaguchi, A. (deposition date: 2013-04-04, release date: 2013-07-03, Last modification date: 2023-11-08)

Primary citation

Nakashima, R.,Sakurai, K.,Yamasaki, S.,Hayashi, K.,Nagata, C.,Hoshino, K.,Onodera, Y.,Nishino, K.,Yamaguchi, A.
Structural basis for the inhibition of bacterial multidrug exporters
Nature, 500:102-106, 2013

PubMed Abstract: The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a π-π interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.

PubMed: 23812586
DOI: 10.1038/nature12300

Experimental method

X-RAY DIFFRACTION (3.05 Å)