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Structure paper

TitleStructural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib.
Journal, issue, pagesCell Rep, Vol. 44, Issue 4, Page 115466, Year 2025
Publish dateMar 25, 2025
AuthorsZhipeng Xie / Jiaxiang Lv / Wei Huang / Zhikun Wu / Rongli Zhu / Zixin Deng / Feng Long /
PubMed AbstractMultidrug 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, ...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.
External linksCell Rep / PubMed:40138312
MethodsEM (single particle)
Resolution2.96 - 3.9 Å
Structure data

39909

8zbs

EMDB-39909, PDB-8zbs:
Cryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (in complex with vincristine)
Method: EM (single particle) / Resolution: 2.96 Å

39910

8zbt

EMDB-39910, PDB-8zbt:
Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
Method: EM (single particle) / Resolution: 3.9 Å

39911

8zbu

EMDB-39911, PDB-8zbu:
Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with lapatinib)
Method: EM (single particle) / Resolution: 3.28 Å

Chemicals

ChemComp-R1Q:
vincristine / medication, chemotherapy*YM

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-URF:
5-FLUOROURACIL / medication, chemotherapy*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-FMM:
N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE / inhibitor*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / ATP-binding cassette sub-family C member 4 / Multidrug resistance proteins (MRPs) / multidrug-resistance (MDR) / TRANSPORT PROTEIN

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