3.A.1.205.4
Multidrug resistance protein, Cdr1 (Candida drug resistance 1) of 1501 aas and 14 TMSs in a CMCM arrangement with each M domain having 7 TMSs in a 6 + 1 TMS arrangement. It confers resistance to cycloheximide, xenobiotics and antifungal agents such as azoles and terbinafine (Holmes et al., 2006; Schuetzer-Muehlbauer et al., 2003); also, transports phospholipids (Shukla et al., 2007). It is the major fluconazole efflux system in fluconazole-resistant C. albicans (Holmes et al., 2008; Basso et al., 2010). Substitution of threonine-1351 results in hypersusceptibility to antifungal agents and threonine-1351 is essential for synergic effects of calcineurin inhibitor FK520 (Shukla et al. 2004). It is similar to Cdr2. For additional details of both systems, as well as other MDR pumps in various Candida species, see Cannon et al., 1998. Chimeras between Cdr1 and Cdr2 revealed regions determining substrate specificity (Tanabe et al., 2011).  The protein has a large polyspecific drug-binding pocket formed by many of the TMSs (Rawal et al. 2013).  The macrocyclic polyketide, FK520, an analologue of antifungal FK506, and a potent immunosuppressant that prevents T-cell proliferation, displays fungicidal synergism with azoles in Candida albicans and inhibits drug efflux mediated by ABC multidrug transporters including Cdr (Nim et al. 2014).  TMS 5 residues impart substrate specificity and selectively act as a communication link between ATP hydrolysis and drug transport (Puri et al. 2009).  The 4 domains (2Cs and 2 Ms) are connected by intracellular loops that allow coupling between ATP hydrolysis and transport  (Shah et al. 2015) and faciliitate membrane targetting (Shah et al. 2015). Multiple drug binding sites have been identified (Nim et al. 2016). The system also transports steroid hormones such as β-estradiol and corticosterone as well as rhodamine 6G using specific but overlapping binding sites (Baghel et al. 2017). The 23-membered-ring macrolide, tacrolimus, a commonly used immunosuppressant also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate, and mutations that minimize its export have been isolated (Tanabe et al. 2018). A structural motif, called the E-helix, plays a role in the maintenance of proper structural fold and/or inter-domain contacts (Vishwakarma et al. 2019). A Q1005H mutant displayed two-fold reduced ATPase activity and two-fold increased drug-resistance as compared to the wild-type protein, pointing to direct control of the non-hydrolytic NBS in substrate-translocation through ATP binding in asymmetric ABC pumps (Banerjee et al. 2019). A functional Cys-deficient Cdr1 protein has been designed (Madani et al. 2021). Milbemycins, enniatin B, beauvericin and FK506 are broad-spectrum fungal multidrug efflux pump inhibitors that inhibit Cdr1, and inhibitor resistant mutants have alterred substrate specificity (Niimi et al. 2021).