Structure and function of a monocarboxylate transporter homolog specific for L-lactate

Area of Science:

• Biochemistry
• Structural Biology
• Cancer Biology

Background:

• Monocarboxylate transporters (MCTs) are crucial for cellular energy metabolism.
• Dysregulation of MCTs is implicated in the progression of various cancers.
• Understanding MCT structure-function is vital for developing targeted cancer therapies.

Purpose of the Study:

• To elucidate the structural basis of L-lactate transport by a solute carrier family 16 homolog.
• To characterize the outward-open conformation of the transporter, relevant for drug development.
• To provide molecular insights into ligand binding and substrate translocation.

Main Methods:

• X-ray crystallography to determine high-resolution transporter structures.
• Biochemical assays to assess substrate and inhibitor binding.
• Structure-function analyses to correlate structural features with transport activity.

Main Results:

• Reported the crystal structures of an L-lactate transporter in complex with its substrate and an inhibitor.
• The determined structures represent the pharmacologically relevant outward-open conformation.
• Structure-function studies revealed key residues involved in ligand recognition and transport.

Conclusions:

• The structural and functional data provide a molecular understanding of L-lactate transport.
• These findings offer a foundation for designing novel inhibitors targeting MCTs in cancer.
• The outward-open conformation provides a template for rational drug design against cancer-associated transporters.