RRC ID 27309
Author Tanaka Y, Hipolito CJ, Maturana AD, Ito K, Kuroda T, Higuchi T, Katoh T, Kato HE, Hattori M, Kumazaki K, Tsukazaki T, Ishitani R, Suga H, Nureki O.
Title Structural basis for the drug extrusion mechanism by a MATE multidrug transporter.
Journal Nature
Abstract Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H(+) or Na(+) across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H(+)-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1-3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.
Volume 496(7444)
Pages 247-51
Published 2013-4-11
DOI 10.1038/nature12014
PII nature12014
PMID 23535598
MeSH Amino Acid Sequence Antiporters / chemistry* Antiporters / metabolism* Apoproteins / chemistry Apoproteins / metabolism Archaeal Proteins / chemistry* Archaeal Proteins / metabolism* Aspartic Acid / chemistry Crystallography, X-Ray DNA Mutational Analysis Macrocyclic Compounds / chemistry Macrocyclic Compounds / metabolism Models, Molecular Molecular Sequence Data Norfloxacin / chemistry Norfloxacin / metabolism Peptides / chemistry Peptides / metabolism Protein Conformation Protons Pyrococcus furiosus / chemistry* Structure-Activity Relationship Sulfides / chemistry Sulfides / metabolism
IF 41.577
Times Cited 87
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material Genomic DNA of Pyrococcus furiosus JCM 8422T (JGD07704)
General Microbes JCM 8422