Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms

• Published in: Pharmacological research Vol. 133; pp. 318 - 327
• Main Authors: Chantemargue, B., Di Meo, F., Berka, K., Picard, N., Arnion, H., Essig, M., Marquet, P., Otyepka, M., Trouillas, P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-07-2018; Elsevier
• Subjects: ABCC4/MRP4 exporter; Atomistic elucidation; Chemical Sciences; In silico pharmacogenomics; Life Sciences; Lipid-protein interactions; Molecular dynamics; Polymorphism and mutation; ABC; Chol; 6-MP; MMA(GS)2; In silico pharmacogenomics; Molecular dynamics; Atomistic elucidation; NBD; ADV; MD; OF; POPC; cryo-EM; IF; WT; DMAV; E217βG; PGE2; ABCC4/MRP4 exporter; RMSD; TMD; ICD; Polymorphism and mutation; MRP4; TMH; ECL; ICL; Lipid-protein interactions; BLOSUM; ITC; AZT; GCV; PMEA; CFTR
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2018.02.029

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The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L1 (linker between the two halves of the exporter); L0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics.