Abstract

Inhibition of interaction between a virus and its receptor is one approach for anti-viral therapy. This proposal is for support of on-going X-ray crystallographic studies of the structure of human CD4, the receptor for HIV. Two different recombinant fragments, containing residues 1-183 and 1- 375 respectively, have been crystallized. The crystals of the """"""""two domain"""""""" fragment CD4 (1-183) permit a structure determination and refinement to 2.5 A resolution. This structure will then be used to aid in determining the structure of the complete extracellular fragment, CD4 (1-375), to at least 4 A resolution. Efforts will also be made to improve the resolution afforded by crystals of CD4 (1-375). Site-directed mutants of Cd4 will be designed to complement existing data, in order to map the precise contact surface for gp 120 and to outline the contact surface for class II MHC antigens. Collaboration with efforts to obtain crystals of gp 120/CD4 complexes is also proposed. The structural results will be useful in the design of anti-HIV agents for treatment of AIDS

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030361-05
Application #
2065566
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1990-07-01
Project End
1996-04-30
Budget Start
1994-05-01
Budget End
1996-04-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Wang, J H; Pepinsky, R B; Stehle, T et al. (1995) The crystal structure of an N-terminal two-domain fragment of vascular cell adhesion molecule 1 (VCAM-1): a cyclic peptide based on the domain 1 C-D loop can inhibit VCAM-1-alpha 4 integrin interaction. Proc Natl Acad Sci U S A 92:5714-8
Karpusas, M; Hsu, Y M; Wang, J H et al. (1995) 2 A crystal structure of an extracellular fragment of human CD40 ligand. Structure 3:1031-9
Wang, J; Pepinsky, B; Karpusas, M et al. (1994) Crystallization and preliminary crystallographic analysis of the N-terminal two domain fragment of vascular cell adhesion molecule-1 (VCAM-1). Proteins 20:287-90
Garrett, T P; Wang, J; Yan, Y et al. (1993) Refinement and analysis of the structure of the first two domains of human CD4. J Mol Biol 234:763-78
Moebius, U; Pallai, P; Harrison, S C et al. (1993) Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding. Proc Natl Acad Sci U S A 90:8259-63
Moebius, U; Clayton, L K; Abraham, S et al. (1992) The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure. J Exp Med 176:507-17
Moebius, U; Clayton, L K; Abraham, S et al. (1992) Human immunodeficiency virus gp120 binding C'C"" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89:12008-12
Harrison, S C; Wang, J; Yan, Y et al. (1992) Structure and interactions of CD4. Cold Spring Harb Symp Quant Biol 57:541-8