7DA5
Cryo-EM structure of the human MCT1 D309N mutant in complex with Basigin-2 in the inward-open conformation.
Summary for 7DA5
| Entry DOI | 10.2210/pdb7da5/pdb |
| Related | 6LYY 6LZ0 7CKO 7CKR |
| EMDB information | 30623 |
| Descriptor | Monocarboxylate transporter 1, Basigin (2 entities in total) |
| Functional Keywords | proton-coupled monocarboxylate transporter, mct1, basigin, azd3965, single particle cryo-em, latate transporter, transport protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 83246.80 |
| Authors | |
| 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 Cited by 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: 33333023DOI: 10.1016/j.cell.2020.11.043 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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