Mechanistic basis of L-lactate transport in the SLC16 solute carrier family

• Published in: Nature communications 2019-06, Vol.10 (1), p.2649-11, Article 2649
• Main Authors: Bosshart, Patrick D., Kalbermatter, David, Bonetti, Sara, Fotiadis, Dimitrios
• Format: Article
• Language: English
• Subjects: 631/45/535/1266; 631/45/612/1237; 631/57/2283; 82/80; 82/83; Amino acids; Bacterial Proteins - chemistry; Bacterial Proteins - isolation & purification; Bacterial Proteins - metabolism; Binding sites; Cancer; Carbon; Cell Membrane - metabolism; Competition; Conformation; Crystal structure; Crystallography, X-Ray; E coli; Homology; Humanities and Social Sciences; Ion Transport - physiology; Lactic acid; Lactic Acid - metabolism; Ligands; Mammalian cells; Membranes; Metabolism; Metabolites; Monocarboxylic Acid Transporters - chemistry; Monocarboxylic Acid Transporters - isolation & purification; Monocarboxylic Acid Transporters - metabolism; multidisciplinary; Muscle Proteins - chemistry; Pharmacology; Plasma membranes; Protein Binding - physiology; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship; Symporters - chemistry; Transport
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10566-6

In human and other mammalian cells, transport of L -lactate across plasma membranes is mainly catalyzed by monocarboxylate transporters (MCTs) of the SLC16 solute carrier family. MCTs play an important role in cancer metabolism and are promising targets for tumor treatment. Here, we report the crystal structures of an SLC16 family homologue with two different bound ligands at 2.54 and 2.69 Å resolution. The structures show the transporter in the pharmacologically relevant outward-open conformation. Structural information together with a detailed structure-based analysis of the transport function provide important insights into the molecular working mechanisms of ligand binding and L -lactate transport. The transport of L -lactate across plasma membranes is catalyzed by proton-driven monocarboxylate transporters (MCTs) of the SLC16 solute carrier family. Here, the authors present the crystal structures of a bacterial SLC16 homologue with the bound substrate L -lactate and ligand thiosalicylate both in an outward-open conformation and discuss the L -lactate transport mechanism.