Back to Search
Start Over
Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.
- Source :
-
Cell . Jan2021, Vol. 184 Issue 2, p370-370. 1p. - Publication Year :
- 2021
-
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. • A data processing strategy for cryo-analysis of small size membrane proteins • Structures of MCT1/Basigin-2 in distinct states at 3.0–3.3 Å resolutions • Substrate recognition and proton-coupled transport mechanism were elucidated • The mode of action of three anti-cancer drug candidates was unveiled Structures of MCT1, a small highly flexible SLC-family transporter, in inward-open and outward open conformations, provide a window on how anti-cancer leads influence transport. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00928674
- Volume :
- 184
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 148140623
- Full Text :
- https://doi.org/10.1016/j.cell.2020.11.043