The Crystal Structure of Mitochondrial Cytochrome bc1 in Complex with Famoxadone:  The Role of Aromatic−Aromatic Interaction in Inhibition^,

Abstract

Ubiquinol cytochrome c oxido-reductase (EC. 1.10.2.2, bc1) is an integral membrane protein complex essential to cellular respiration. Structures of the 11-subunit mitochondrial bc1 complex were determined with and without the fungicide famoxadone. Specific inhibition by famoxadone is achieved through a coordinated optimization of aromatic-aromatic interactions where conformational rearrangements in famoxadone and in residues lining the inhibitor-binding pocket produce a network of aromatic-aromatic interactions that mimic the crystal lattice of benzene. The profound aromatic-aromatic interactions as supported by prior mutagenesis provide a structural basis for specific protein-ligand interaction in a hydrophobic environment. Dramatic conformational changes, both in cyt. b and ISP subunits in the inhibitor-protein complex, confer experimental evidence for a functional role of cytochrome b in the induced conformational arrest of ISP and allow the identification of a possible intrasubunit signal transduction pathway that controls the movement of ISP. These results support an inhibitory mechanism that is consistent with the requirement for ISP movement in the electron transfer of this complex.

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

“…We note, for example, that the wild rat from Copenhagen possesses two missense substitutions (H93Q, A94P) in the cytochrome b gene (Cytb) not observed in any other strain. These residues are next to one of the iron-containing heme groups, as judged by the position of these residues in the highly conserved bovine homolog, whose three-dimensional structure has been deduced (30). This wild rat had missense substitutions in the three genes that did not contain any such substitutions in our sample (Cytb, ND1, and COIII), as well as substitutions in two tRNA genes (tRNA-glutamine and tRNA-serine-1) that otherwise had no polymorphisms in our 12 rats.…”

Inhibitor-complexed Structures of the Cytochrome bc1 from the Photosynthetic Bacterium Rhodobacter sphaeroides

“…1, A and B, Supplemental Table S2). The a 0 -helix reaches to the cyt b of its symmetry mate and forms a pair of salt bridges between Arg 22 and Glu 126 of the symmetry-related cyt b and a number of hydrogen bonds as well as van der Waals interactions (Fig. 1, A and B).…”

Intraprotein transfer of the quinone analogue inhibitor 2,5-dibromo-3-methyl-6-isopropyl- p -benzoquinone in the cytochrome b 6 f complex

“…X-ray structures of the dimeric b 6 f complex have been obtained from the thermophilic cyanobacterium Mastigocladus laminosus (2) in the native state (3.4 Å), in the presence of the p-side quinone analogue inhibitor tridecyl-stigmatellin (TDS) [3.0 Å; Protein Data Bank (PDB) ID code 1VF5] or 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB) (3.8 Å; PDB ID code 2D2C), and from the green alga, Chlamydomonas reinhardtii, cocrystallized with TDS (3.1 Å; PDB ID code 1Q90) (3). These structures define binding sites of quinol analogue inhibitors that could be compared with data on the binding sites of p-side inhibitors obtained from x-ray structure analysis of the mitochondrial bc 1 complex (4)(5)(6)(7)(8)(9)(10)(11).…”

“…Crystallographic analysis of the bc 1 and b 6 f complexes has defined a large p-side quinone-binding (Q p ) space (2)(3)(4)(5)(6)(7)(8)(9)(10)(11), in which most of the reactive head groups of these inhibitors reside in a pocket (Q p ) and the tails, if present, extend into a narrow portal connecting the pocket to the large intermonomer quinone-exchange cavity. The Q p space is portrayed in Fig.…”