Structural basis of polyspecific drug recognition by MRP2
Ishimoto, N.; Kadonoff, H.; McGuigan, E.; Yousof, L.; Roumeliotis, T. I.; Choudhary, J. S.; Linton, K. J.; Beis, K.
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Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a hepatobiliary ATP-binding cassette transporter that mediates the efflux of endogenous conjugates and many therapeutic agents, yet the basis of its broad ligand specificity remains poorly understood. Here we combine cryo-electron microscopy, ATPase measurements and cell-based transport inhibition assays to define how MRP2 recognizes clinically relevant compounds from distinct chemical classes. We find that chemically diverse ligands occupy overlapping regions of a shared transmembrane cavity but adopt different poses, contact networks and stoichiometries. Ligand recognition is mediated predominantly by a permissive environment complemented by ligand-specific polar interactions, rather than by a single conserved pharmacophore. These findings establish a structural framework for MRP2 polyspecificity and provide insight into hepatobiliary drug disposition and transporter-mediated drug-drug interactions.
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