Structural and biochemical analyses uncovered the substrate binding and transport mechanisms of MCT1.

  • Major Finding: Structural and biochemical analyses uncovered the substrate binding and transport mechanisms of MCT1.

  • Concept: MCT1–Basigin-2 inhibitors caused different structural changes but were all competitive inhibitors.

  • Impact: This study reveals the inhibition mechanism of MCTs, which can be targeted for anticancer therapies.

Monocarboxylate transporters (MCT) are key components involved in monocarboxylate absorption and redistribution in mammalian cells and are known to play a role in cancer development by increasing lactate shuttling, prompting the development of MCT inhibitors. In an effort to better understand the mechanism by which these inhibitors reduce MCT activity, Wang, Jiang, and colleagues determined the cryo-EM structures of the human MCT1 complex (comprised of MCT1 and the chaperone protein Basigin-2) and the MCT1 complex bound to lactate or to the inhibitors AZD3965, BAY-8002, and 7ACC2 at resolutions of 3.0 to 3.3. Comparison of cryo-EM structures showed that substrate translocation occurred via protonation-dependent rigid-body rotation of two domains to expose a binding site on each side of the membrane. This idea was supported by the finding that the complex adopted a distinct outward-open structure when lactate or the inhibitors BAY8002 or AZD3965 were bound and an inward-open structure when the inhibitor 7ACC2 was bound. Despite these structural differences, all the inhibitors blocked MCT1 activity via competitive inhibition. This was supported by a structural comparison between lactate- and inhibitor-bound human MCT1. Notably, AZD3965 (which is currently in phase I clinical trials as an anticancer therapy) is known to have subtype-specific sensitivities as it inhibits MCT1/2, but not MCT4. The structural mapping of the key residues involved in AZD3965 binding suggests this could be attributed to sequence variation between MCT subtypes. In summary, this study shows how three MCT1 inhibitors interact with the MCT1 complex to disrupt normal transporter activity. The structures of human MCT1–Basigin-2 bound to the MCT1 inhibitors provide key insight into the molecular mechanism of how substrate translocation is blocked, providing a strong foundation for the structure-guided development of MCT1 inhibitors for cancer treatment.

Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 2020;184:370–83.E13.

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