Structural basis of resistance to anti-cytochrome bc? complex inhibitors: implication for drug improvement.

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 bc? 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 bc? inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc? 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 bc? 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.

SUBMITTER: Esser L 

PROVIDER: S-EPMC4788501 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature