title: Structural basis of resistance to anti-cytochrome bc₁ 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 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.
authors.forename: Lothar
authors.initials: L
authors.lastname: Esser
authors.forename: Chang-An
authors.initials: CA
authors.lastname: Yu
authors.affiliation: Laboratory of Cell Biology, NCI, NIH, 37 Convent Dr., Building 37, Room 2122C, Bethesda MD 20892. dixia@helix.nih.gov.
authors.forename: Di
authors.initials: D
authors.lastname: Xia
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D004351:Drug Resistance; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D058451:Oxidative Coupling / Q000187:drug effects; D018892:Proton-Motive Force / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D014450:Electron Transport Complex III