Structural Basis for the Quinone Reduction in the bc1 Complex: A Comparative Analysis of Crystal Structures of Mitochondrial Cytochrome bc1 with Bound Substrate and Inhibitors at the Qi Site,

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Abstract
Cytochrome bc1 is an integral membrane protein complex essential to cellular respiration and photosynthesis. The Q cycle reaction mechanism of bc1 postulates a separated quinone reduction (Qi) and quinol oxidation (Qo) site. In a complete catalytic cycle, a quinone molecule at the Qi site receives two electrons from the bH heme and two protons from the negative side of the membrane; this process is specifically inhibited by antimycin A and NQNO. The structures of bovine mitochondrial bc1 in the presence or absence of bound substrate ubiquinone and with either the bound antimycin A1 or NQNO were determined and refined. A ubiquinone with its first two isoprenoid repeats and an antimycin A1 were identified in the Qi pocket of the substrate and inhibitor bound structures, respectively; the NQNO, on the other hand, was identified in both Qi and Qo pockets in the inhibitor complex. The two inhibitors occupied different portions of the Qi pocket and competed with substrate for binding. In the Qo pocket, the NQNO behaves similarly to stigmatellin, inducing an iron−sulfur protein conformational arrest. Extensive binding interactions and conformational adjustments of residues lining the Qi pocket provide a structural basis for the high affinity binding of antimycin A and for phenotypes of inhibitor resistance. A two-water-mediated ubiquinone protonation mechanism is proposed involving three Qi site residues His201, Lys227, and Asp228.

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