The crystal structure of mitochondrial cytochrome bc1 in complex with famoxadone: the role of aromatic-aromatic interaction in inhibition.
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.
Gao
Xiugong
X
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wen
Xiaolin
X
Yu
ChangAn
C
Esser
Lothar
L
Tsao
Scott
S
Quinn
Byron
B
Zhang
Li
L
Yu
Linda
L
Xia
Di
D
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003460:Crystallization; D018360:Crystallography, X-Ray; D003573:Cytochrome b Group / Q000737:chemistry; D004579:Electron Transport; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006873:Hydroquinones / Q000737:chemistry; D020128:Inhibitory Concentration 50; D046911:Macromolecular Substances; D008689:Methacrylates; D008929:Mitochondria, Heart / Q000201:enzymology*; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D000073739:Strobilurins
D003573:Cytochrome b Group; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D046911:Macromolecular Substances; D008689:Methacrylates; D010080:Oxazoles; D021122:Protein Subunits; D000073739:Strobilurins; D014450:Electron Transport Complex III; C401929:famoxadone