Structural basis for xenobiotic extrusion by eukaryotic MATE transporter.

Area of Science:

• Structural biology
• Molecular biology
• Biochemistry

Background:

• Multidrug and Toxic Compound Extrusion (MATE) transporters are crucial for cellular homeostasis, exporting xenobiotics and drugs.
• While human MATEs handle xenobiotics and clinical drugs, plant MATEs are involved in aluminum tolerance and secondary metabolite transport.

Purpose of the Study:

• To elucidate the structure and transport mechanism of eukaryotic MATE transporters.
• To provide insights for improving the pharmacokinetics of clinical drugs.

Main Methods:

• X-ray crystallography to determine the structure of the Arabidopsis thaliana MATE transporter at 2.6 Å resolution.
• Structure-based mutational analysis to investigate the function of conserved residues.

Main Results:

• The crystal structure reveals a conserved hydrogen-bonding network in the carboxy-terminal lobe (C-lobe) involving acidic residues.
• Protonation of these acidic residues induces a hydrogen-bonding network, leading to structural changes in transmembrane helix 7.
• This mechanism is proposed to be central to the transport function of eukaryotic MATE transporters.

Conclusions:

• The study provides the first crystal structure of a eukaryotic MATE transporter.
• The findings elucidate a novel transport mechanism involving protonation-induced conformational changes.
• This structural and mechanistic understanding is vital for optimizing drug pharmacokinetics.