3.D.4.6.2
Cytochrome c aa₃ oxidase (COX). The 3-d structure is known (PDB# 1M56) (Lee et al., 2012).  There are three hydrophobic channels connecting the hydrophobic membrane through the protein to the heme A₃/Cu_B binuclear center (BNC), two of which are probably preferred for O₂ diffusion (Oliveira et al. 2014). The D channel is the proton transporting channel, and mutations in residues along this channel, especially N139 in subunit 1, uncouple H⁺ transport from electron flow (Han et al. 2005). Liang et al. 2017 provided insight into the decoupling mechanisms of CcO mutants, and explained how kinetic gating in the D-channel is imperative to achieving high proton-pumping efficiency in the WT CcO. The O₂ molecules that arrived in the reduction site diffuse through the X-ray-observed tunnel, despite its apparent constriction, supporting its role as the main O₂ delivery pathway in cytochrome aa3 (Mahinthichaichan et al. 2018).