3tgu

Cytochrome bc1 complex from chicken with pfvs-designed moa inhibitor bound

spinqualitylabelsall models 3tgu, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tgu is a 20 chain structure with sequence from Gallus gallus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BOG, CDL, FES, GOL, HEC, HEM, PEE, UNL, UQ, WF3 NonStd Res: AME, FME, UNK Related: 3l71 Activity: Ubiquinol--cytochrome-c reductase, with EC number 1.10.2.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [D0VX30_CHICK] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain (By similarity).[PIRNR:PIRNR000022] [CYB_CHICK] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis (By similarity). [UCRI_CHICK] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis (By similarity). [D0VX28_CHICK] This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1.[PIRNR:PIRNR000019] Publication Abstract from PubMed A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K(i) = 83.00 pM) bound to the chicken bc(1) at 2.70 A resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques. Computational Discovery of Picomolar Q(o) Site Inhibitors of Cytochrome bc(1) Complex.,Hao GF, Wang F, Li H, Zhu XL, Yang WC, Huang LS, Wu JW, Berry EA, Yang GF J Am Chem Soc. 2012 Jun 27. PMID:22690928 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome bc1 complex

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