Recent advances in genome research have revealed that over one-third of open reading frames in yeast (S. cerevisiae) are predicted to be integral membrane proteins with one to fourteen transmembrane segments, reflecting the importance of membrane proteins in the life cycle of this unicellular eukaryotic organism. In multicellular organisms, cellular communication and interaction require increased biological complexity and likely an increased fraction of membrane proteins. Membrane proteins provide vital cellular functions involved in cell- cell communication, recognition, adhesion, and membrane fusion, and also in material exchange, transport and in processes of cellular energy conservation. Structural studies on a limited number of membrane proteins have contributed to our understanding of the function of these biological macromolecules. In the light of the increased number of membrane proteins being studied, the paucity of atomic structural data on membrane proteins creates a vacuum in our knowledge which is being filled rather slowly. To date, only a few families of membrane protein structures have been determined; most of them are involved in photosynthesis and respiration. The situation arises mainly due to tremendous difficulties or the near impossibility of purifying a sufficient quantity of most membrane proteins needed for structural analysis and in producing diffraction quality crystals. We, in collaboration with both intramural and extramural laboratories, explore the structure and function relations of polytopic membrane proteins crystallographically by examining a few carefully selected membrane proteins such as those involved in cellular multidrug resistance (human P-glycoprotein) and respiration (cytochrome bc1complex). We hope that these studies will result in a deep understanding of membrane protein architecture in general, the mechanism of function of these important biological membrane proteins, and in development of therapeutics. - membrane protein complexes, Biochemistry, Cancer, computational biology, computer modeling, Drug Discovery, Drug resistance, drug transport, membrane proteins, molecular structure, Oxidation/reduction, protein structure, protein-protein interaction, proteolysis, - Neither Human Subjects nor Human Tissues

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010319-01
Application #
6289383
Study Section
Special Emphasis Panel (LCB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Li, Yong-Fu; Polgar, Orsolya; Okada, Masaki et al. (2007) Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study. J Mol Graph Model 25:837-51
Xia, Di; Esser, Lothar; Yu, Linda et al. (2007) Structural basis for the mechanism of electron bifurcation at the quinol oxidation site of the cytochrome bc1 complex. Photosynth Res 92:17-34
Kim, In-Wha; Peng, Xiang-Hong; Sauna, Zuben E et al. (2006) The conserved tyrosine residues 401 and 1044 in ATP sites of human P-glycoprotein are critical for ATP binding and hydrolysis: evidence for a conserved subdomain, the A-loop in the ATP-binding cassette. Biochemistry 45:7605-16
Ambudkar, Suresh V; Kim, In-Wha; Xia, Di et al. (2006) The A-loop, a novel conserved aromatic acid subdomain upstream of the Walker A motif in ABC transporters, is critical for ATP binding. FEBS Lett 580:1049-55
Gurung, Buddha; Yu, Linda; Xia, Di et al. (2005) The iron-sulfur cluster of the Rieske iron-sulfur protein functions as a proton-exiting gate in the cytochrome bc(1) complex. J Biol Chem 280:24895-902
Gong, Xing; Yu, Linda; Xia, Di et al. (2005) Evidence for electron equilibrium between the two hemes bL in the dimeric cytochrome bc1 complex. J Biol Chem 280:9251-7
Esser, Lothar; Quinn, Byron; Li, Yong-Fu et al. (2004) Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc(1) complex. J Mol Biol 341:281-302
Gao, Xiugong; Wen, Xiaoling; Esser, Lothar et al. (2003) Structural basis for the quinone reduction in the bc1 complex: a comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site. Biochemistry 42:9067-80