*1.1. ABC Transporters and Clinical Relevance of MDR*

The ATP-binding cassette (ABC) transporter family is one of the largest protein superfamilies present in all living organisms, from prokaryotes to eukaryotes [1–5]. ABC transporters can operate as exporters or importers in an ATP-dependent manner, and mediate the membrane translocation of bewildering substrate spectra against concentration gradients [6–8]. In addition, ABC proteins can function as ion channels, channel regulators, receptors, proteases, protein sensors or are even involved in mRNA translation and ribosome biogenesis [9–11]. Remarkably, conserved architectures offer specific yet broad substrate-binding regions and somehow form a translocation path that operates in a unidirectional way in eukaryotes. The wide substrate range includes cationic anticancer drugs, antifungal drugs, steroids, phospholipids, bile acids, antibiotics, peptides, ions, heavy metals, carbohydrates and glucocorticoids, as well as toxins [12–15]. The hallmark domain organization of ABC transporters entails four core units, two evolutionarily conserved nucleotide-binding domains (NBDs) and two transmembrane-spanning domains (TMDs), typically consisting of twelve hydrophobic transmembrane-spanning helices (TMHs). These four domains are normally arranged as a full-transporter in a single protein

**Citation:** Khunweeraphong, N.; Kuchler, K. Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms. *Int. J. Mol. Sci.* **2021**, *22*, 4806. https://doi.org/10.3390/ijms22094806

Academic Editor: Thomas Falguières

Received: 25 March 2021 Accepted: 28 April 2021 Published: 30 April 2021

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as TMD1–NBD1–TMD2–NBD2 or in a reverse configuration NBD1–TMD1–NBD2–TMD2. Alternatively, half-transporters come in NBD–TMD or TMD–NBD arrangements, which require at least homo- or hetero-dimerization for a functional complex [16–19]. In addition, some members contain additional domains or motifs such as the TMD0 domain or the R-domain regulatory motif [8,20,21].

The NBD is a universally conserved domain that consumes ATP and somehow fuels the dynamic switch of the transporter structure from an inward substrate-binding state to an outward substrate-releasing conformation. The catalytic cycle drives the conformational switch at the TMD and enables the substrate translocation through an as yet elusive transport pathway [22,23]. The TMDs are more diverse in sequence and show much less conservation, but clearly are essential for forming putative substrate translocation pores. They must handle a broad spectrum of chemically diverse substrates and inhibitors [24,25]. Notably, the communication between NBD and TMD and the dynamics underlying the entire transport cycle of ABC transporters remain unclear. While certain elements or stages of the transport cycles may be conserved among subfamilies, the expanding number of atomic structures and the resulting mechanistic information for distinct ABC transporters make unifying mechanisms less likely, challenging earlier notions about a unified catalytic cycle [8,16,17,26–45]. No matter what the actual catalytic cycle or mechanism of a given type I or type II exporter may be, a tantalizing possibility is that a basic conserved mechanism operates for PDR and ABCG, but slightly different transport mechanisms could be a consequence of the nature of substrates that would distinctly affect the kinetics and dynamics of the cycle.

The human ABC transporter family of 48 genes served to categorize subfamilies into the ABCA to ABCG nomenclature [46–48], although the surge of recent atomic structures and functional considerations made it clear that a new and improved nomenclature based on structure–function relationships is needed [43]. Remarkably, inborn errors of several human ABC transporters lead to prominent genetic diseases [49], including cystic fibrosis (ABCC7 or CFTR) [50,51], hepatic cholestasis (ABCB11 or BSEP) [52,53], plant sterol sitosterolemia (ABCG5/G8) [54–57], neonatal hyperinsulinemic hypoglycemia or noninsulin-dependent childhood diabetes (ABCC8) [58], gout (ABCG2 or BCRP) [59], Dubin– Johnson syndrome (ABCC2 or MRP2) [60,61] and Stargardt's macular dystrophies and retinophathies (ABCA4) [62], peroxisomal adrenoleukodystrophy or ALD (ABCD1) [63–65], immune deficiency—class I MHC antigen presentation (ABCB2/B3, TAP) [66–68], cholesterol transport and HDL assembly or Tangier's disease (ABCA1, ABCG1) [69–75], pseudoxanthoma elasticum or PXE (ABCC6) [76–82], dilated cardiomyopathy (ABCC9) [83], defective earwax synthesis (ABCC11) [84,85], lung surfactant deficiency (ABCA3) [86–89], lamella and harlequin ichthyosis (ABCA12) [90–92], pregnancy-related cholestasis (ABCB4) [93,94] and sideroblastic anemia (ABCB7) [95–98].
