6LYY

Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate AZD3965 in the outward-open conformation.

Summary for 6LYY

• Entry DOI: 10.2210/pdb6lyy/pdb
• Related: 6LZ0 7CKO 7CKR 7DA5
• EMDB information: 30019 30020 30389 30391 30623
• Descriptor: Monocarboxylate transporter 1, Basigin, 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione (3 entities in total)
• Functional Keywords: proton-coupled monocarboxylate transporter, mct1, basigin, anti-cancer, azd3965, bay-8002, 7acc2, single particle cryo-em, latate transporter, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 83763.30

Authors

Wang, N.,Jiang, X.,Zhang, S.,Zhu, A.,Yuan, Y.,Lei, J.,Yan, C. (deposition date: 2020-02-16, release date: 2020-12-23, Last modification date: 2024-03-27)

Primary citation

Wang, N.,Jiang, X.,Zhang, S.,Zhu, A.,Yuan, Y.,Xu, H.,Lei, J.,Yan, C.
Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.
Cell, 184:370-, 2021

PubMed 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.

PubMed: 33333023
DOI: 10.1016/j.cell.2020.11.043

Experimental method

ELECTRON MICROSCOPY (3.2 Å)