8ZBS
Cryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (in complex with vincristine)
Summary for 8ZBS
| Entry DOI | 10.2210/pdb8zbs/pdb |
| EMDB information | 39909 |
| Descriptor | ATP-binding cassette sub-family C member 4, vincristine, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total) |
| Functional Keywords | atp-binding cassette sub-family c member 4, multidrug resistance proteins (mrps), multidrug-resistance (mdr), transport protein, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 154089.51 |
| Authors | |
| Primary citation | Xie, Z.,Lv, J.,Huang, W.,Wu, Z.,Zhu, R.,Deng, Z.,Long, F. Structural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib. Cell Rep, 44:115466-115466, 2025 Cited by PubMed Abstract: Multidrug resistance proteins (MRPs) are one of the major mechanisms for developing cancer drug resistance. Human MRP4 (hMRP4) plays an important role in various chemotherapy-resistant cancers. Here, we show hMRP4 mediates the resistance of a broad spectrum of antitumor reagents in the cultured tumor cells, among which the cell resistance to vincristine and 5-fluorouracil is rescued by supplementing a tyrosinase inhibitor, lapatinib. The cryoelectron microscopy (cryo-EM) structures of hMRP4 in the substrate- or inhibitor-bound form are determined. Although lapatinib shares partial binding sites with vincristine and 5-fluorouracil using a similar set of crucial residues located in the central cavity of hMRP4, the high binding affinity of lapatinib and its unique binding mode with transmembrane helices TM2 and TM12 inside the pathway tunnel prohibit hMRP4 from structural transition between intermediate states during drug translocation. This study provides mechanistic insights into the therapeutical potential of lapatinib in combating hMRP4-mediated MDR. PubMed: 40138312DOI: 10.1016/j.celrep.2025.115466 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.96 Å) |
Structure validation
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