3.A.1.122.1
Macrolide (14- and 15- but not 16-membered lactone macrolides including erythromycin) exporter, MacAB (formerly YbjYZ). Both MacA and MacB are required for activity (Tikhonova et al., 2007). MacAB functions with TolC to export multiple drugs and heat-stable enterotoxin II (enterotoxin STII) (Yamanaka et al., 2008). The crystal structure of MacA is available (Yum et al., 2009). MacB is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA (Lin et al., 2009). Xu et al. (2009) have reported the crystal structure of the periplasmic region of MacB which they claim resembles the periplasmic domain of RND-type transporters such as AcrB (TC# 2.A.6.2.2). Also exports L-cysteine (Yamada et al., 2006). The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by the MacB transporter (Modali and Zgurskaya, 2011). Fitzpatrick et al. 2017 presented an electron cryo-microscopy structure of the tripartite assembly (MacAB-TolC) at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges a TolC trimer in the outer membrane to a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA may act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism (Fitzpatrick et al. 2017). The structure of ATP-bound MacB has been solved, revealing precise molecular details of its mechanism (Crow et al. 2017). MacB has a fold that is different from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores (Greene et al. 2018).