3AOD

Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket

Summary for 3AOD

• Entry DOI: 10.2210/pdb3aod/pdb
• Related: 3AOA 3AOB 3AOC
• Descriptor: Acriflavine resistance protein B, (4S,4AS,5AR,12AS)-4,7-BIS(DIMETHYLAMINO)-3,10,12,12A-TETRAHYDROXY-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDROTETRACENE-2- CARBOXAMIDE, RIFAMPICIN, ... (4 entities in total)
• Functional Keywords: membrane protein, inner membrane, membrane protein-antibiotic complex, membrane protein/antibiotic
• Biological source: Escherichia coli
• Cellular location: Cell inner membrane ; Multi- pass membrane protein : P31224
• Total number of polymer chains: 3
• Total formula weight: 343933.64

Authors

Nakashima, R.,Sakurai, K.,Yamaguchi, A. (deposition date: 2010-09-23, release date: 2011-11-30, Last modification date: 2023-11-01)

Primary citation

Nakashima, R.,Sakurai, K.,Yamasaki, S.,Nishino, K.,Yamaguchi, A.
Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket
Nature, 480:565-569, 2011

PubMed Abstract: AcrB and its homologues are the principal multidrug transporters in Gram-negative bacteria and are important in antibiotic drug tolerance. AcrB is a homotrimer that acts as a tripartite complex with the outer membrane channel TolC and the membrane fusion protein AcrA. Minocycline and doxorubicin have been shown to bind to the phenylalanine cluster region of the binding monomer. Here we report the crystal structures of AcrB bound to the high-molecular-mass drugs rifampicin and erythromycin. These drugs bind to the access monomer, and the binding sites are located in the proximal multisite binding pocket, which is separated from the phenylalanine cluster region (distal pocket) by the Phe-617 loop. Our structures indicate that there are two discrete multisite binding pockets along the intramolecular channel. High-molecular-mass drugs first bind to the proximal pocket in the access state and are then forced into the distal pocket in the binding state by a peristaltic mechanism involving subdomain movements that include a shift of the Phe-617 loop. By contrast, low-molecular-mass drugs, such as minocycline and doxorubicin, travel through the proximal pocket without specific binding and immediately bind to the distal pocket. The presence of two discrete, high-volume multisite binding pockets contributes to the remarkably broad substrate recognition of AcrB.

PubMed: 22121023
DOI: 10.1038/nature10641

Experimental method

X-RAY DIFFRACTION (3.3 Å)