3.A.1.210.6
Mitochondrial outer membrane/lysosome anionic porphyrin uptake half ABC transporter, ABCB6. It is expressed in many mammalian tissues (including fetal liver) in response to intracellular porphyrin. Porphyrin uptake activates de novo porphyrin (haem) biosynthesis (Krishnamurthy et al., 2006).  The first TMS contains a lysosomal targetting signal (Kiss et al. 2015). It transports toxic metals and anti-cancer drugs. The cryo EM structure has been determined (Wang et al. 2020). A slit-like substrate binding pocket may accommodate the planar shape of porphyrins, and the existence of a secondary cavity near the mitochondrial intermembrane space side may further facilitate substrate release. Song et al. 2021 determined the cryo-EM structures of nanodisc-reconstituted human ABCB6 trapped in an apo-state and an ATP-bound state at resolutions of 3.6 and 3.5 Å, respectively. The structures revealed a unique loop in the transmembrane domain (TMD) of ABCB6, which divides the TMD into two cavities. It restrains the access of substrates in the inward-facing state and is removed by ATP-driven conformational changes. No ligand cavities were observed in the nucleotide-bound state, indicating a state following substrate release but prior to ATP hydrolysis. Structural analyses and functional characterization suggest an "ATP-switch" model and further reveal the conformational changes of the substrate-binding pockets triggered by the ATP-driven regulation (Song et al. 2021). ABCB6, ABCG2, FECH and CPOX are expressed in meningioma tissue (Spille et al. 2023).  ABCB6 as an oncogene suggests promising avenues for targeted therapies in KIRP, LIHC, and PAAD (Xiao et al. 2024).