2. Academic Validation
  3. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates

Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates

  • Cell. 2021 Jan 21;184(2):370-383.e13. doi: 10.1016/j.cell.2020.11.043.
Nan Wang 1,  Xin Jiang 2,  Shuo Zhang 1,  Angqi Zhu 1,  Yafei Yuan 1,  Hanwen Xu 1,  Jianlin Lei 3,  Chuangye Yan 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: xin.jiang@unsw.edu.au.
  • 3 Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: yancy2019@tsinghua.edu.cn.
PMID: 33333023 DOI: 10.1016/j.cell.2020.11.043
Abstract

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.

Keywords

7ACC2; AZD3965; BAY-8002; Basigin/CD147; MCT; SLC transporters; alternating access; cryo-EM; lactate transport; monocarboxylate transporter; proton coupling.

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