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PDBsum entry 1sqv

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Oxidoreductase PDB id
1sqv
Jmol
Contents
Protein chains
446 a.a.
423 a.a.
378 a.a.
241 a.a.
196 a.a.
105 a.a.
75 a.a.
67 a.a.
57 a.a.
61 a.a.
51 a.a.
Ligands
HEM ×3
UHD
UQ2
FES
Waters ×291

References listed in PDB file
Key reference
Title Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc(1) complex.
Authors L.Esser, B.Quinn, Y.F.Li, M.Zhang, M.Elberry, L.Yu, C.A.Yu, D.Xia.
Ref. J Mol Biol, 2004, 341, 281-302. [DOI no: 10.1016/j.jmb.2004.05.065]
PubMed id 15312779
Abstract
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.
Figure 1.
Figure 1. Structures of cyt b and ISP subunit in the bc[1] complex. A, Ribbon diagram of the dimeric cyt b and ISP in the bc[1] complex. Two cyt b subunits (labeled cyt b in light blue and cyt b-sym in green, respectively) and two ISP subunits (labeled ISP in yellow and ISP-sym in red, respectively) related by a molecular 2-fold symmetry are shown. The eight TM helices of cyt b are named sequentially from A to H. The two b-type hemes labeled b[L] and b[H] are shown as the ball-and-stick models. Two active sites in the cyt b are labeled: one is the quinone reduction site (Q[i]) and the other is the quinol oxidation site (Q[o]). The surface depression in cyt b on the inter-membrane space (IMS) side is labeled as the ISP-docking crater for interacting with the ISP. B, Stereo pair: structural environment of the native Q[o] site. The Q[o] pocket is depicted as a GRASP[64.] surface with the surrounding secondary structure elements. Helices cd1, cd2, and ef as well as parts of C, B E and F helices are shown and labeled. The heme b[L] of cyt b, 2Fe-2S cluster of the ISP, and the conserved residues that are in contact with bound inhibitors in the bc[1]-inhibitor complexes are also shown in the ball-and-stick form. Carbon atoms are colored yellow, oxygen red, nitrogen blue and sulfur green.
Figure 5.
Figure 5. Structural environments for the class Pf inhibitors. Bound inhibitors at the Q[o] pocket are shown in stick form and carbon atoms are shown in black, nitrogen in blue and oxygen in red. The inhibitors are enclosed in the cage of difference electron density calculated with refined phases with the inhibitor molecule omitted. Secondary structure elements around the Q[o] site of cyt b are given. Helices cd1, cd2, and ef as well as parts of C, B and E helices are shown and as labeled. The heme b[L] of cyt b and the iron-sulfur cluster of the ISP are also shown in the ball-and-stick form. Residues in the Q[o] pocket that are in direct contact with the inhibitor are rendered as stick models, in which carbon atoms are colored yellow, sulfur green, oxygen red and nitrogen blue. Those residues whose mutations render bc[1] inhibitor resistant and are in direct contact with the inhibitor are colored magenta for the carbon atoms. All difference maps are contoured at 3s except for that of UHDBT, which is at 2s. A, Stereo pair: stigmatellin binding environment. The stigmatellin is labeled as STG in red. B, Stereo pair: UHDBT binding environment. C, Stereo pair: famoxadone binding environment. The famoxadone is labeled FAM in red. D, Stereo pair: NQNO binding environment.
The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 341, 281-302) copyright 2004.
Secondary reference #1
Title Crystal structure of the cytochrome bc1 complex from bovine heart mitochondria.
Authors D.Xia, C.A.Yu, H.Kim, J.Z.Xia, A.M.Kachurin, L.Zhang, L.Yu, J.Deisenhofer.
Ref. Science, 1997, 277, 60-66. [DOI no: 10.1126/science.277.5322.60]
PubMed id 9204897
Full text Abstract
Figure 2.
Fig. 2. Anomalous scattering difference-Fourier map contoured at 5.1 (red) and difference densities between inhibitor-bound and^ native crystals contoured at 4.5 (antimycin A) and 4.0 (myxothiazol). (A) View parallel to the membrane plane, with the intermembrane^ space at the top and the matrix space at the bottom. Peaks were^ assigned to hemes b[H], b[L], and c[1] and to the Rieske iron-sulfur cluster, respectively, as shown. Distances between some iron pairs are indicated (see Table 2). The twofold symmetry axis of the^ bc[1] dimer (purple line) runs in the plane of the diagram. (B) View perpendicular to the membrane plane.
Figure 3.
Fig. 3. Inhibitor binding sites in the cytochrome bc[1] complex. (A) Stereo diagram of the antimycin A binding pocket. The helices a, A, D, and E of cytochrome b form the pocket as shown. The DE^ loop is the bottom, and the b[H] heme (yellow ball-and-stick model) is the back wall of the pocket. The difference density between inhibitor-bound and native crystals is contoured at 4.5 (blue) and at -4.5 (brown). An antimycin molecule is fitted to the positive^ density. (B) Stereo diagram of the myxothiazol binding pocket, formed by helices C, F, cd1, and ef of cytochrome b, as indicated. The b[L] heme (yellow ball-and-stick model) and the Rieske^ iron-sulfur center (green and yellow dots) are about equally distant from the pocket. The difference density is contoured at 4.0 (blue).
The above figures are reproduced from the cited reference with permission from the AAAs
Secondary reference #2
Title The crystal structure of mitochondrial cytochrome bc1 in complex with famoxadone: the role of aromatic-Aromatic interaction in inhibition.
Authors X.Gao, X.Wen, C.Yu, L.Esser, S.Tsao, B.Quinn, L.Zhang, L.Yu, D.Xia.
Ref. Biochemistry, 2002, 41, 11692-11702. [DOI no: 10.1021/bi026252p]
PubMed id 12269811
Full text Abstract
PROCHECK
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