Cytochrome bc1 complex [2Fe-2S] cluster and its interaction with ubiquinone and ubihydroquinone at the Qo site: a double-occupancy Qo site model

Ding, Huangen; Robertson, Dan E.; Daldal, Fevzi; Dutton, P. Leslie

doi:10.1021/bi00127a015

Cited by 206 publications

(285 citation statements)

References 55 publications

(106 reference statements)

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“…Since the residues contributing to these functions are not a common set, mutations might be expected at the different interfaces, at either of which changes could modify the function of the site. The extensive work from Ding et al (34)(35)(36)(37) on occupancy of the site in different mutant strains as reflected in the g x ) 1.80 signal of the [2Fe-2S] center has contributed a valuable set of data on interactions of the occupant with the ISP. In collaboration with Ding and Dutton, we have made similar measurements on some of our mutant strains from Rb.…”

Section: Distribution Of Residues At Which Mutation Results In Modifimentioning

confidence: 99%

“…However, we cannot rule out such a possibility. If future work shows that two quinones can occupy the Q o site, some modification of the model of Ding et al (34,35) would be needed. From the structure, it is clear that all interactions with the ISP must occur from the distal domain, and the pattern of mutational change suggests that the g x ) 1.800 signal reflects an interaction of Q in this domain with ISP red .…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of inhibitors, the spectrum reflects the state of the quinone pool (31)(32)(33)(34)(35)(36)(37). When the Q pool is oxidized, a signal at the g x ) 1.800 is observed.…”

Section: Structure Of the Q O Sitementioning

confidence: 99%

“…Further information on the occupancy of the Q o site has been obtained though study of the interaction of the occupant with the [2Fe-2S] center of the reduced ISP, observed through changes in the EPR spectrum. In addition to the effects observed with stigmatellin and UHDBT (23)(24)(25)(26), a well-defined spectral change giving rise to a band at g x ) 1.80 has been characterized when quinone and the reduced ISP are both present (31)(32)(33)(34)(35)(36)(37). The dependence on ambient redox potential, and on the extent of extraction of quinone, has lead Ding and colleagues to suggest a double occupancy of the site by weakly (Q ow ) and strongly (Q os ) binding quinone species (34)(35)(36)(37).…”

mentioning

confidence: 99%

“…The dependence on ambient redox potential, and on the extent of extraction of quinone, has lead Ding and colleagues to suggest a double occupancy of the site by weakly (Q ow ) and strongly (Q os ) binding quinone species (34)(35)(36)(37). Inhibitors of either class eliminate EPR signals ascribed to both species (34,35). Support for occupancy of the Q o site by more than one species has been suggested by Brandt et al (30) on the basis of kinetic studies interpreted as showing noncompetitive binding of MOA-type inhibitors in the presence of substrate quinol.…”

mentioning

confidence: 99%

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Mechanism of Ubiquinol Oxidation by the bc₁ Complex: Different Domains of the Quinol Binding Pocket and Their Role in the Mechanism and Binding of Inhibitors

et al. 1999

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Structures of mitochondrial ubihydroquinone:cytochrome c oxidoreductase (bc 1 complex) from several animal sources have provided a basis for understanding the functional mechanism at the molecular level. Using structures of the chicken complex with and without inhibitors, we analyze the effects of mutation on quinol oxidation at the Q o site of the complex. We suggest a mechanism for the reaction that incorporates two features revealed by the structures, a movement of the iron sulfur protein between two separate reaction domains on cytochrome c 1 and cytochrome b and a bifurcated volume for the Q o site. The volume identified by inhibitor binding as the Q o site has two domains in which inhibitors of different classes bind differentially; a domain proximal to heme b L , where myxothiazole and -methoxyacrylate-(MOA-) type inhibitors bind (class II), and a distal domain close to the iron sulfur protein docking interface, where stigmatellin and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiaole (UHDBT) bind (class I). Displacement of one class of inhibitor by another is accounted for by the overlap of their volumes, since the exit tunnel to the lipid phase forces the hydrophobic "tails" to occupy common space. We conclude that the site can contain only one "tailed" occupant, either an inhibitor or a quinol or one of their reaction products. The differential sensitivity of strains with mutations in the different domains is explained by the proximity of the affected residues to the binding domains of the inhibitors. New insights into mechanism are provided by analysis of mutations that affect changes in the electron paramagnetic resonance (EPR) spectrum of the iron sulfur protein, associated with its interactions with the Q o -site occupant. The structures show that all interactions with the iron sulfur protein must occur at the distal position. These include interactions between quinone, or class I inhibitors, and the reduced iron sulfur protein and formation of a reaction complex between quinol and oxidized iron sulfur protein. The step with high activation energy is after formation of the reaction complex, likely in formation of the semiquinone and subsequent dissociation of the complex into products. We suggest that further progress of the reaction requires a movement of semiquinone to the proximal position, thus mapping the bifurcated reaction to the bifurcated volume. We suggest that such a movement, together with a change in conformation of the site, would remove any semiquinone formed from further interaction with the oxidized [2Fe-2S] center and also from reaction with O 2 to form superoxide anion. We also identify two separate reaction paths for exit of the two protons released in quinol oxidation.The ubiquinol:cytochrome c oxidoreductases family of enzymes (the bc 1 complexes) 1 are central components of many electron-transfer systems, occurring ubiquitously in respiratory and photosynthetic chains of mitochondria and bacteria and (as the b 6 f complex) in the photosynthetic chain of oxygenic photosynth...

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Section: Distribution Of Residues At Which Mutation Results In Modifimentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…In the absence of inhibitors, the spectrum reflects the state of the quinone pool (31)(32)(33)(34)(35)(36)(37). When the Q pool is oxidized, a signal at the g x ) 1.800 is observed.…”

Section: Structure Of the Q O Sitementioning

confidence: 99%