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Crystal structures of multidrug efflux pump MexB bound with high-molecular-mass compounds.
Sakurai, Keisuke; Yamasaki, Seiji; Nakao, Kaori; Nishino, Kunihiko; Yamaguchi, Akihito; Nakashima, Ryosuke.
Afiliação
  • Sakurai K; Laboratory of Cell Membrane Structural Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, 567-0047, Japan.
  • Yamasaki S; Department of Biomolecular Science and Regulation, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, 567-0047, Japan.
  • Nakao K; Department of Biomolecular Science and Regulation, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, 567-0047, Japan.
  • Nishino K; School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan.
  • Yamaguchi A; Department of Biomolecular Science and Regulation, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, 567-0047, Japan.
  • Nakashima R; School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan.
Sci Rep ; 9(1): 4359, 2019 03 13.
Article em En | MEDLINE | ID: mdl-30867446
RND-type multidrug efflux pumps have two voluminous multisite drug-binding pockets named the proximal and distal binding pocket. High- and low-molecular-mass drugs bind to these proximal and distal pocket, respectively. Here, we report the crystal structures of MexB of Pseudomonas aeruginosa bound with high-molecular-mass compounds. Contrary to the expectations, lauryl maltose neopentyl glycol (LMNG, MW 1,005), which is a surfactant larger than the proximal pocket-binding drugs, was found to bind to the distal pocket: one of the two hydrophobic alkyl chains was inserted into the hydrophobic pit, which is the binding site of the efflux pump inhibitor ABI-PP. LMNG is a substrate of the MexAB-OprM system and competitively inhibits the export of other substrates by this system. However, LMNG does not inhibit the export of other substrates by the inhibitor-binding-pit mutant F178W, which retains the export activity of LMNG. The crystal structure of this mutant suggested that the alkyl chain of LMNG could no longer be inserted into the pit because of steric hindrance. We also determined the crystal structure of MexB containing the high-molecular-mass compound neopentyl glycol derivative C7NG (MW 1,028), the binding site of which overlapped with LMNG in the distal pocket, indicating that whether a substrate binds to the distal or proximal pockets is controlled not only by its molecular weight but also by its individual molecular characteristic.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Proteínas da Membrana Bacteriana Externa / Modelos Moleculares / Ligantes Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Proteínas da Membrana Bacteriana Externa / Modelos Moleculares / Ligantes Idioma: En Ano de publicação: 2019 Tipo de documento: Article