**1. Introduction**

The ATP-binding cassette (ABC) proteins constitute one of the largest families of membrane proteins. They are universally present in all kingdoms of life. In humans, 48 functional genes encode for ABC proteins, which on the basis of structural and sequence similarity are categorized into seven subfamilies, designated as ABCA through G [1]. Most of these proteins transport substrates across cellular membranes. A functional ABC transporter comprises at least four domains: two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs), as shown in Figure 1. In the ABCB subfamily, each of the TMDs consists of six membrane-spanning helices. Five of these extend into the cytoplasm to form an expansive intracellular domain. The two TMDs are responsible for substrate binding and translocation. The NBDs form two composite nucleotide-binding sites (NBSs) at their interface, which bind and hydrolyze ATP, and thereby provide the energy for substrate transport. These NBSs are formed by the Walker A and Walker B motifs, as well as the A-, Q- and H-loops of one NBD and the signature motif and D-loop of the other NBD [2,3].

**Citation:** Sohail, M.I.; Dönmez-Cakil, Y.; Szöll˝osi, D.; Stockner, T.; Chiba, P. The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies. *Int. J. Mol. Sci.* **2021**, *22*, 784. https://doi.org/10.3390/ ijms22020784

Received: 29 December 2020 Accepted: 12 January 2021 Published: 14 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Schematic of the four-domain architecture of an ATP-binding cassette (ABC) transporter, as illustrated for the bile salt export pump BSEP. Hydrolysis of ATP by the nucleotide binding domains (NBD) energizes transport of bile salts from the hepatocyte cytoplasm to the bile canaliculus. Transmembrane domains (TMD) form the path for bile salt transport across the canalicular membrane.

The ABCB subfamily is one of the most diverse groups of ABC proteins, as it includes dimeric half transporters, monomers of which are each composed of one TMD and one NBD, but also full-length transporters, in which all four domains are fused into a single polypeptide chain. The former group comprises the homodimeric transporters ABCB6, ABCB7, ABCB8, ABCB9 and ABCB10, and the heterodimeric transporter ABCB2/ABCB3. The four full-length transporters of the ABCB subfamily are ABCB1, ABCB4, ABCB5 and ABCB11. The heterodimeric ABCB2/ABCB3 and full-length ABCB11 differ from the other members as they contain only one canonical NBS rather than two [4].
