The primary objective is to determine the three-dimensional structures of the gag encoded human immunodeficiency virus (HIV) proteins that participate in the formation of the viral capsid. It is anticipated that the structure of the HIV capsid (CA) protein (p24) or the HIV matrix (MA) protein (pl7) are likely targets for antiviral agents that might inhibit assembly or uncoating. The X-ray crystallographic structure determination of HIV-1 p24, currently in progress, is likely to be successful in the next year, certainly in the next two years. Completion of the structure determination may require further heavy atom derivative data sets (about three reasonable and solved derivatives are on hand), analysis of anomalous dispersion data or analysis of other p24:Fab crystal forms to be averaged with the first. In addition, it will be necessary to determine the amino acid sequence of the Fab fragment used in the crystallization process, by isolating the predominant mRNA from the hybridoma. The structure of HIV p24 will permit analysis of possible binding sites of small organic ligands which would stabilize the proteins and, hence, inhibit assembly or uncoating in a manner similar to the successful development of antiviral agents to human rhinoviruses. Theoretical docking techniques and experimental diffusion of possible ligands into the crystals will be attempted. The structure will permit the mapping of the surface epitopes presented by the virus in early stages of infection as well as analysis of the various functions associated with the capsid protein (CA) by rational site-directed mutagenesis. Work on other gag related proteins, particularly of HIV pl7 and the p55 gag precursor, has been initiated with the same objective of eventually finding assembly and uncoating inhibitors.
| Kingston, R L (2001) Locating the anomalous scatterers within a crystal using dual-wavelength X-ray diffraction measurements. Acta Crystallogr D Biol Crystallogr 57:101-7 |
| Yu, F; Joshi, S M; Ma, Y M et al. (2001) Characterization of Rous sarcoma virus Gag particles assembled in vitro. J Virol 75:2753-64 |
| Kingston, R L; Olson, N H; Vogt, V M (2001) The organization of mature Rous sarcoma virus as studied by cryoelectron microscopy. J Struct Biol 136:67-80 |
