Abstract

Five investigators seek program support for structural studies of macromolecules and molecular interactions related to the etiology and control of AIDS. The program has three main objectives: 1. Determination of molecular structures (Eiserling/Eisenberg/Dickerson/Rees). To provide the fundamental structural information needed for rational drug design, structures will be determined for: the HIV envelope glycoprotein and its complexes with monoclonal antibodies and the T4 (CD4) lymphocyte receptor (Eiserling/Eisenberg/Rees), and the HIV reverse transcriptase (Dickerson). Biological materials will be supplied from the laboratories of Dr. L. Lasky (Genentech) and Dr. L. Hood (Caltech). To insure the availability of crystalline specimens for structural studies, the Core facilities for cystallization and coordinated electron microscopy and diffraction will be enhanced. To permit more rapid collection of x-ray data, diffraction equipment will be improved. 2. Molecular recognition and drug design (Dickerson/Sigman/Eisenberg/Rees). Principles of DNA-drug interactions will be developed (Dickerson). Designs for sequence-specific DNA-cutting orthophenanthrolines will be extended and applied to HIV (Sigman). Characterizations of molecular surfaces by their atomic solvation parameters and surface roughness will be extended and applied to drug binding (Rees/Eisenberg). To assure biological relevance of the work, the following scientists have agreed to consult or to collaborate as the work proceeds: Dr. James Paulson (UCLA; glycoproteins); Dr. L. Lasky (Genentech; HIV genes and proteins); Dr. L. Hood (Caltech; proteins of the immune system); Dr. O. Witte and Dr. R. Gaynor (UCLA; virology); Dr. J. Feigon (UCLA; NMR and intermolecular interactions). To permit increased emphasis on characterization of interactions and drug design, facilities for computation and graphics will be improved. 3. Training (Core and all five principal laboratories). A major effort will be undertaken to provide training in principles and practice of structural determination and molecular interactions for graduate students and postdoctorals. Three one quarter graduate courses are currently offered (by the five investigators) that provide fundamentals of biological structure and interactions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM039558-05
Application #
3096324
Study Section
Special Emphasis Panel (SRC (08))
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Fahrner, R L; Dieckmann, T; Harwig, S S et al. (1996) Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes. Chem Biol 3:543-50
Peterson, R D; Feigon, J (1996) Structural change in Rev responsive element RNA of HIV-1 on binding Rev peptide. J Mol Biol 264:863-77
Schneider, D J; Feigon, J; Hostomsky, Z et al. (1995) High-affinity ssDNA inhibitors of the reverse transcriptase of type 1 human immunodeficiency virus. Biochemistry 34:9599-610
Perrin, D M; Mazumder, A; Sadeghi, F et al. (1994) Hybridization of a complementary ribooligonucleotide to the transcription start site of the lacUV-5-Escherichia coli RNA polymerase open complex. Potential for gene-specific inactivation reagents. Biochemistry 33:3848-54
Pearson, L; Chen, C B; Gaynor, R P et al. (1994) Footprinting RNA-protein complexes following gel retardation assays: application to the R-17-procoat-RNA and tat--TAR interactions. Nucleic Acids Res 22:2255-63
Perrin, D M; Pearson, L; Mazumder, A et al. (1994) Inhibition of prokaryotic and eukaryotic transcription by the 2:1 2,9-dimethyl-1,10-phenanthroline-cuprous complex, a ligand specific for open complexes. Gene 149:173-8
Peterson, R D; Bartel, D P; Szostak, J W et al. (1994) 1H NMR studies of the high-affinity Rev binding site of the Rev responsive element of HIV-1 mRNA: base pairing in the core binding element. Biochemistry 33:5357-66
Mazumder, A; Perrin, D M; McMillin, D et al. (1994) Interactions of transcription inhibitors with the Escherichia coli RNA polymerase-lacUV5 promoter open complex. Biochemistry 33:2262-8
Sklenar, V; Peterson, R D; Rejante, M R et al. (1994) Correlation of nucleotide base and sugar protons in a 15N-labeled HIV-1 RNA oligonucleotide by 1H-15N HSQC experiments. J Biomol NMR 4:117-22
Sklenar, V; Peterson, R D; Rejante, M R et al. (1993) Two- and three-dimensional HCN experiments for correlating base and sugar resonances in 15N,13C-labeled RNA oligonucleotides. J Biomol NMR 3:721-7

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