Structural Basis of Resistance to Anti-Cytochrome bc₁ Complex Inhibitors: Implication for Drug Improvement

Title:Structural Basis of Resistance to Anti-Cytochrome bc₁ Complex Inhibitors: Implication for Drug Improvement

Volume: 20 Issue: 5

Author(s): Lothar Esser, Chang-An Yu and Di Xia

Affiliation:

Keywords: cyt bc₁ complex, mechanism of inhibition, crystal structure, resistance, inhibitors.

Abstract: The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc₁ inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc₁ complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc₁ by various quinol oxidation- and reductionsite inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives.

Cite this article as:

Esser Lothar, Yu Chang-An and Xia Di, Structural Basis of Resistance to Anti-Cytochrome bc₁ Complex Inhibitors: Implication for Drug Improvement, Current Pharmaceutical Design 2014; 20 (5) . https://dx.doi.org/10.2174/138161282005140214163327