Schematic representation of ABC protein architecture, misfolding and correction with pharmacochaperones. (a) Architecture of folded protein. The two halves of a full transporter are shown in light and dark blue. TMDs and ICLs are shown as rectangles, NDBs as circles. C and α refer to the core (F1 type) and the α-helical subdomains of NBD, respectively. Parts of the TMD-NBD interface are formed by engagement of ICL2 (ICL4) into the socket between C and α subdomain of the respective contralateral NBD. (b) Misfolded protein – incorrect formation of TMD-NBD interface. (c) Misfolded protein – misfolding of one NBD. (d) Position of one substrate binding site in the TMD of correctly folded protein (orange circle). (e) Correction of misfolded domain interface by pharmacochaperone (yellow circle) bound to substrate binding site (orange). (f) Correction of misfolded protein with one disrupted NBD. Rescue might require direct binding of corrector molecule (green circle) to exosite of NBD (blue circle). Alternatively, an active site compound might also correct folding, by providing the scaffold of a correctly positioned ICL 2/4 to the respective NBD. NBD, nucleotide binding domain; TMD, transmembrane domain; ICL, intracellular loop. Pharmacological correction of misfolding of ABC proteins. Rudashevskaya EL, Stockner T, Trauner M, Freissmuth M, Chiba P - Drug discovery today. Technologies (2014). Not Altered. CC.