Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.
By Nan Wang, Xin Jiang, Shuo Zhang, A. Zhu, Yafei Yuan, Hanwen Xu, Jianlin Lei, Chuangye Yan. 2020
299 citations recorded by the source corpus.
Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs.
Subfields: Molecular Biology
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Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, background): “…characterized in the literature ( Drew and Boudker, 2016 ), including rocking-bundle (LAT1, Yan et al., 2019 ; Yan et al., 2021 ; ZnT8, Xue et al., 2020 ), rocker-switch (MCT1, Wang et al., 2021 ; STP10, Bavnhøj et al., 2021 ), and elevator (ASCT2, Garibsingh et al., 2021 ; Garaeva et al., 2019 ).”