Structure of an ABC transporter in complex with its binding protein

Area of Science:

• Structural Biology
• Biochemistry
• Molecular Mechanisms of Transport

Background:

• ATP-binding cassette (ABC) transporters are crucial membrane proteins involved in nutrient uptake and drug resistance.
• Bacterial ABC importers are essential for nutrient acquisition, while ABC exporters can cause multidrug resistance in cancer.
• High-resolution structures are needed to understand the distinct conformations and mechanisms of ABC transporters.

Purpose of the Study:

• To determine the high-resolution crystal structure of the Archaeoglobus fulgidus molybdate transporter (ModB2C2) complexed with its binding protein (ModA).
• To elucidate the structural basis of substrate translocation in ABC importers.
• To compare the mechanism of ModB2C2A with known ABC exporters like Sav1866.

Main Methods:

• X-ray crystallography to obtain a 3.1 Å resolution structure of the ModB2C2A complex.
• Structural analysis of the transmembrane domains (ModB) and nucleotide-binding domains (ModC).
• Comparative structural analysis with the multidrug ABC exporter Sav1866.

Main Results:

• The ModB2C2A structure reveals an inward-facing conformation of the transmembrane helices (ModB) with a closed gate.
• The nucleotide-binding domains (ModC) are in a nucleotide-free, open conformation.
• The binding protein (ModA) positions the substrate-binding cleft towards the transporter's internal pathway.

Conclusions:

• The ModB2C2A structure provides insights into the mechanism of nutrient uptake by bacterial ABC importers.
• Structural comparison with Sav1866 suggests a conserved alternating access and release mechanism for both importers and exporters.
• ATP binding likely drives outward-facing conformations, while hydrolysis product dissociation favors inward-facing conformations.