Redox-coupled quinone dynamics in the respiratory complex I

Abstract

SignificanceComplex I is the primary energy-converting enzyme of aerobic respiratory chains. By reducing quinone to quinol, this gigantic enzyme pumps protons across its membrane domain, which in turn powers ATP synthesis and active transport. Despite the recently resolved molecular structures of complex I, the quinone dynamics and its coupling to the pumping function remains unclear. Here we show by large-scale molecular simulations that the quinone reduction leads to ejection of the quinol molecule from the active site into a second binding site near the proton-pumping membrane domain of complex I. The identified region has been linked with human mitochondrial disorders. Our work suggests that the quinone dynamics provides a key coupling element in complex I.

Pseudomonas Quinolone Signal molecule PQS behaves like a B Class inhibitor at the I Q site of mitochondrial complex I

“…An analogous partially competitive inhibition with regard to ubiquinone was reported for the I Q site inhibitor Piericidin A . The mixed‐inhibition type is consistent with the notion that several Q‐binding sites and different binding positions of quinone‐site inhibitors may exist within the quinone channel . The two inhibition constants representing the competitive and uncompetitive components of the inhibition ( K i,c and K i,u ) were 0.56 and 0.12 µmol/L, respectively.…”

“…32,33 The mixed-inhibition type is consistent with the notion that several Q-binding sites and different binding positions of quinone-site inhibitors may exist within the quinone channel. [34][35][36][37][38] The two inhibition constants representing the competitive and uncompetitive components of the inhibition (K i,c and K i,u ) were 0.56 and 0.12 µmol/L, respectively. Complex I retained a low residual activity of 15.8% even at saturating concentrations of PQS, possibly due to leakage of electrons from prosthetic groups such as FMN to DCPIP.…”

Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

“…Our data indicate that the conformational switching takes place via a conserved network of ion pairs between the N-and M-domains of the enzyme involving, e.g., E381 ( Supplementary Figs. 7 and 19), with mechanistic similarities to, e.g., respiratory complex I, a mitochondrial redox-driven proton pump where quinone reduction triggers proton pumping, up to 200 Å from the active site, by conformational changes in a network of conserved ion pairs [34][35][36][37] . It is puzzling that although the R32A variant is not viable in vivo and unable to properly form a closed compact state, the enzyme still hydrolyses ATP with an unchanged ADP-release rate.…”

Effects of lipid composition on membrane distribution and permeability of natural quinones

“…[1][2][3][4] Clearly, the mechanisms for molecular recognition and binding of Q by respiratory and photosynthetic enzymatic (super)complexes 5,6 depend on the membrane distribution of Q molecules. [7][8][9] Diffusion of Q in the membrane has also been suggested to control ETC turnover rates. [10][11][12][13] In redox loops translocating protons across the membrane directly through a quinone/ quinol pair (or pool), as in the Q-cycle, 14,15 at least two events of Q permeation, or transversal diffusion, occur.…”