Abstract

The approaches outlined in Part I suggest new routes to obtaining homogeneous complexes of CD4 and HIV gp120. Crystallization of these complexes, which involve the two-domain fragment CD4 (1-183) and various deglycosylate and truncated derivatives of gp120, will be attempted. The goal is determination of a three-dimensional structure of the CD4/gp120 complex by X-ray diffraction to whatever resolution the crystals will afford. Further knowledge of the structure of this complex will be important for design of compounds that block viral attachment or that inactivate HIV by mimicking CD4. In addition, efforts will be made to determine the structure of complexes of CD4 (1-183) with compounds already available that interfere with the CD4/gp120 interaction. Two strategies will be attempted: co-crystallization of the compounds with CD4(1-183), and diffusion of the compounds into CD4(1-183)/Fab co- crystals. The determination of one or more such structures will permit more rational design of actual drug candidates.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AI027336-09S1
Application #
6099272
Study Section
Project Start
1996-12-01
Project End
1998-09-30
Budget Start
Budget End
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Ferrer, M; Harrison, S C (1999) Peptide ligands to human immunodeficiency virus type 1 gp120 identified from phage display libraries. J Virol 73:5795-802
Tan, K; Liu, J; Wang, J et al. (1997) Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc Natl Acad Sci U S A 94:12303-8
Ferrer, M; Godbout, K L; Sullivan, B J et al. (1997) Construction and characterization of a radio-iodinatable mutant of recombinant human CD4. J Immunol Methods 210:215-25
Sakihama, T; Smolyar, A; Reinherz, E L (1995) Oligomerization of CD4 is required for stable binding to class II major histocompatibility complex proteins but not for interaction with human immunodeficiency virus gp120. Proc Natl Acad Sci U S A 92:6444-8
Sakihama, T; Smolyar, A; Reinherz, E L (1995) Molecular recognition of antigen involves lattice formation between CD4, MHC class II and TCR molecules. Immunol Today 16:581-7
Bell, K D; Ramilo, O; Vitetta, E S (1993) Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus. Proc Natl Acad Sci U S A 90:1411-5
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
Ghetie, V; Wheeler, T; Scott, D et al. (1992) A CD4-derived peptide carrier blocks acute HIV-1 infection in vitro and binds to gp120 in the presence of Walter-Reed stage 1-6 HIV+ sera. AIDS Res Hum Retroviruses 8:1945-8

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