Structural Basis of Resistance to Anti-Cytochrome bc1 Complex Inhibitors: Implication for Drug Improvement
Lothar Esser, Chang-An Yu and Di Xia
Affiliation: Laboratory of Cell Biology, NCI, NIH, 37 Convent Dr., Building 37, Room 2122C, Bethesda MD 20892.
Keywords: cyt bc1 complex, mechanism of inhibition, crystal structure, resistance, inhibitors.
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.
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