Considerable progress has been achieved on mapping the receptor binding site of cationic biogenic amine hormones, however, little progress has been made on determining the nature of the binding site of G-protein coupled receptors that bind peptide ligands of sizes that range from three (fMLP) to several hundred residues (LH and FSH). It is clear that all G- protein coupled receptors share some common structural features, however, there are also major differences with regard to the binding domain. In this proposal we choose to elucidate the binding domain of the interleukin-8 receptor which belongs to the superfamily of G-protein coupled receptors. Interleukin-8 (IL-8) is a 72 amino acid peptide secreted by many cell types in response to proinflammatory stimuli such as interleukin-1, and tumor necrosis factor. IL-8 induces transendothelial migration cloning of Interleukin-8 receptor subtypes exhibiting novel ligand binding specificity with regard to structurally related peptides, neutrophil activating peptide 2 (NAP-2) and melanoma growth stimulating activity (MGSA). We determined that the ligand binding specificity is dictated by the extracellular N-terminus to identify the residues at the IL-8/receptor interface by using a genetic approach. Mapping the amino acid residues at the ligand-receptor interface will aid toward the design of novel IL-8 receptor antagonists that will impact in the treatment of inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034031-02
Application #
2069100
Study Section
Physiology Study Section (PHY)
Project Start
1994-09-01
Project End
1999-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Physiology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Navarro, Javier; Landau, Ehud M; Fahmy, Karim (2002) Receptor-dependent G-protein activation in lipidic cubic phase. Biopolymers 67:167-77
Suetomi, Katsutoshi; Rojo, Daniel; Navarro, Javier (2002) Identification of a signal transduction switch in the chemokine receptor CXCR1. J Biol Chem 277:31563-6
Suetomi, K; Lu, Z; Heck, T et al. (1999) Differential mechanisms of recognition and activation of interleukin-8 receptor subtypes. J Biol Chem 274:11768-72
Wilkinson, N C; Navarro, J (1999) PU.1 regulates the CXCR1 promoter. J Biol Chem 274:438-43
Sanchez, X; Suetomi, K; Cousins-Hodges, B et al. (1998) CXC chemokines suppress proliferation of myeloid progenitor cells by activation of the CXC chemokine receptor 2. J Immunol 160:906-10
Sanchez, X; Cousins-Hodges, B; Aguilar, T et al. (1997) Activation of HIV-1 coreceptor (CXCR4) mediates myelosuppression. J Biol Chem 272:27529-31
Prado, G N; Suzuki, H; Wilkinson, N et al. (1996) Role of the C terminus of the interleukin 8 receptor in signal transduction and internalization. J Biol Chem 271:19186-90