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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The ABCC4/MRP4 transporter is crucial for drug disposition and its dysfunction increases drug toxicity risk.
• No human MRP4 structure was previously available, hindering molecular understanding of its dysfunctions.

Purpose of the Study:

• To construct an atomistic model of wild-type (WT) MRP4 and the p.Gly187Trp mutant.
• To elucidate the molecular basis of MRP4 dysfunction caused by genetic variations.

Main Methods:

• Molecular dynamics simulations of WT and mutant MRP4 in lipid bilayers.
• Atomistic modeling and structural analysis.

Main Results:

• The WT MRP4 model confirmed known structural features and elucidated previously unresolved domains (L0, L1, zipper helices).
• The p.Gly187Trp mutation significantly impacted the NBD1 structure and flexibility of MRP4.
• The structural model rationalizes known MRP4 dysfunctions linked to polymorphisms.

Conclusions:

• The developed MRP4 model provides molecular insights into drug transport and toxicity.
• This resource facilitates in silico prediction of the impact of other MRP4 mutations on drug transport.
• Enables advancements in predictive pharmacogenetics for personalized medicine.