Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc(1) complex.
Cytochrome bc(1) is an integral membrane protein complex essential for cellular respiration and photosynthesis; it couples electron transfer from quinol to cytochrome c to proton translocation across the membrane. Specific bc(1) inhibitors have not only played crucial roles in elucidating the mechanism of bc(1) function but have also provided leads for the development of novel antibiotics. Crystal structures of bovine bc(1) in complex with the specific Q(o) site inhibitors azoxystrobin, MOAS, myxothiazol, stigmatellin and 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole were determined. Interactions, conformational changes and possible mechanisms of resistance, specific to each inhibitor, were defined. Residues and secondary structure elements that are capable of discriminating different classes of Q(o) site inhibitors were identified for the cytochrome b subunit. Directions in the displacement of the cd1 helix of cytochrome b subunit in response to various Q(o) site inhibitors were correlated to the binary conformational switch of the extrinsic domain of the iron-sulfur protein subunit. The new structural information, together with structures previously determined, provide a basis that, combined with biophysical and mutational data, suggest a modification to the existing classification of bc(1) inhibitors. bc(1) inhibitors are grouped into three classes: class P inhibitors bind to the Q(o) site, class N inhibitors bind to the Q(i) site and the class PN inhibitors target both sites. Class P contains two subgroups, Pm and Pf, that are distinct by their ability to induce mobile or fixed conformation of iron-sulfur protein.
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Lothar
L
Esser
Byron
B
Quinn
Yong-Fu
YF
Li
Minquan
M
Zhang
Maria
M
Elberry
Linda
L
Yu
Chang-An
CA
Yu
Di
D
Xia
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006912:Hydroxyquinolines / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D011090:Polyenes / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D006912:Hydroxyquinolines; D011090:Polyenes; C010494:nonyl-4-hydroxyquinoline-N-oxide; C041573:stigmatellin; D014450:Electron Transport Complex III