3VVR

Crystal structure of MATE in complex with MaD5

3VVR の概要

• エントリーDOI: 10.2210/pdb3vvr/pdb
• 関連するPDBエントリー: 3VVN 3VVO 3VVP 3VVQ 3VVS
• 分子名称: Putative uncharacterized protein, macrocyclic peptide, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (4 entities in total)
• 機能のキーワード: mate, multidrug transporter, macrocyclic peptide, transport protein, transport protein-inhibitor complex, transport protein/inhibitor
• 由来する生物種: Pyrococcus furiosus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51444.15

構造登録者

Tanaka, Y.,Ishitani, R.,Nureki, O. (登録日: 2012-07-27, 公開日: 2013-04-03, 最終更新日: 2024-10-16)

主引用文献

Tanaka, Y.,Hipolito, C.J.,Maturana, A.D.,Ito, K.,Kuroda, T.,Higuchi, T.,Katoh, T.,Kato, H.E.,Hattori, M.,Kumazaki, K.,Tsukazaki, T.,Ishitani, R.,Suga, H.,Nureki, O.
Structural basis for the drug extrusion mechanism by a MATE multidrug transporter.
Nature, 496:247-251, 2013

PubMed 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.

PubMed: 23535598
DOI: 10.1038/nature12014

実験手法

X-RAY DIFFRACTION (3 Å)