3TGU

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

Summary for 3TGU

• Entry DOI: 10.2210/pdb3tgu/pdb
• Related: 3L71
• Descriptor: Mitochondrial ubiquinol-cytochrome-c reductase complex core protein i, Mitochondrial ubiquinol-cytochrome c reductase 7.2 kda protein, UNKNOWN LIGAND, ... (21 entities in total)
• Functional Keywords: cytochrome bc1, membrane protein, heme protein, rieske iron sulfur protein, cytochrome b, cytochrome c1, complex iii, mitochondrial processing protein, ubiquinone, oxidoreductase, redox enzyme, respiratory chain, electron transport, heme, inner membrane, membrane, strobilurins binding, mitochondrion, transmembrane, iron, mitochondrial inner membrane, iron-sulfur, transit peptide, metal-binding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Gallus gallus (bantam,chickens); More
• Total number of polymer chains: 20
• Total formula weight: 486604.17

Authors

Huang, L.-S.,Yang, G.-F.,Berry, E.A. (deposition date: 2011-08-17, release date: 2012-07-04, Last modification date: 2023-09-13)

Primary citation

Hao, G.F.,Wang, F.,Li, H.,Zhu, X.L.,Yang, W.C.,Huang, L.S.,Wu, J.W.,Berry, E.A.,Yang, G.F.
Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.
J.Am.Chem.Soc., 134:11168-11176, 2012

PubMed Abstract: 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 Å 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.

PubMed: 22690928
DOI: 10.1021/ja3001908

Experimental method

X-RAY DIFFRACTION (2.7 Å)