PDBsum entry 3aoc

Membrane protein/antibiotic

PDB id: 3aoc

Contents

Protein chains

1022 a.a.

Ligands

ERY

Waters ×5

PDB id:

3aoc

Name:

Membrane protein/antibiotic

Title:

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

Structure:

Acriflavine resistance protein b. Chain: a, b, c. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: acrb, acre, b0462, ecdh1_3148, jw0451. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

3.34Å R-factor: 0.277 R-free: 0.344

Authors:

R.Nakashima,K.Sakurai,A.Yamaguchi

Key ref:

R.Nakashima et al. (2011). Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature, 480, 565-569. PubMed id: 22121023

Date:

23-Sep-10 Release date: 30-Nov-11

Protein chains

P31224  (ACRB_ECOLI) -  Multidrug efflux pump subunit AcrB from Escherichia coli (strain K12)

Seq: 1049 a.a.

Struc: 1022 a.a.

Nature 480:565-569 (2011)

PubMed id: 22121023

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

R.Nakashima, K.Sakurai, S.Yamasaki, K.Nishino, A.Yamaguchi.

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.