論文 - 詳細
| RRC ID | 27309 |
|---|---|
| 著者 | 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. |
| タイトル | Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. |
| ジャーナル | 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. |
| 巻・号 | 496(7444) |
| ページ | 247-51 |
| 公開日 | 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 | 42.779 |
| 引用数 | 149 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 79 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | Genomic DNA of Pyrococcus furiosus JCM 8422T (JGD07704) |
| 一般微生物 | JCM 8422 |