Recent work has shown that packaging of the cellular protein cyclophilin A plays an important role in HIV-1 replication. Cyclophilin A incorporates into HIV-1 virions by virtue of binding to CA. To understand this interaction, the investigator will determine the crystal structure of cyclophilin A bound to a truncated form of CA. The truncated form binds cyclophilin A with the same affinity as full-length CA, but is a monomer rather than a dimer. Preliminary results show co-crystals that diffract to 2.5 A. In addition, binding of cyclophilin to a capsid peptide will be characterized biochemically and structurally. In particular the conformation of Pro90 in CA bound to cyclophilin A suggests that this residue may act as a substrate for cyclophilin rotamase activity. Finally, genetic analysis of mutants of CA in an HIV provirus will be used to test models that arise from the CA and CA-cyclophilin structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040333-04
Application #
6163712
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Bridges, Sandra H
Project Start
1997-03-01
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
4
Fiscal Year
2000
Total Cost
$222,950
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Worthylake, D K; Wang, H; Yoo, S et al. (1999) Structures of the HIV-1 capsid protein dimerization domain at 2.6 A resolution. Acta Crystallogr D Biol Crystallogr 55:85-92
von Schwedler, U K; Stemmler, T L; Klishko, V Y et al. (1998) Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly. EMBO J 17:1555-68
Vajdos, F F; Yoo, S; Houseweart, M et al. (1997) Crystal structure of cyclophilin A complexed with a binding site peptide from the HIV-1 capsid protein. Protein Sci 6:2297-307
Gamble, T R; Yoo, S; Vajdos, F F et al. (1997) Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein. Science 278:849-53
Yoo, S; Myszka, D G; Yeh, C et al. (1997) Molecular recognition in the HIV-1 capsid/cyclophilin A complex. J Mol Biol 269:780-95