Mitochondrial Cytochrome bc₁ Complex as Validated Drug Target: A Structural Perspective

Mitochondrial respiratory chain Complex III, also known as cytochrome bc₁ complex or cyt bc₁, is a validated target not only for antibiotics but also for pesticides and anti-parasitic drugs. Although significant progress has been made in understanding the mechanisms of cyt bc₁ function and inhibition by using various natural and synthetic compounds, important issues remain in overcoming drug resistance in agriculture and in evading cytotoxicity in medicine. In this review, we look at these issues from a structural perspective. After a brief description of the essential and common structural features, we point out the differences among various cyt bc₁ complexes of different organisms, whose structures have been determined to atomic resolution. We use a few examples of cyt bc₁ structures determined via bound inhibitors to illustrate both conformational changes observed and implications to the Q-cycle mechanism of cyt bc₁ function. These structures not only offer views of atomic interactions between cyt bc₁ complexes and inhibitors, but they also provide explanations for drug resistance when structural details are coupled to sequence changes. Examples are provided for exploiting structural differences in evolutionarily conserved enzymes to develop antifungal drugs for selectivity enhancement, which offer a unique perspective on differential interactions that can be exploited to overcome cytotoxicity in treating human infections.