Bioconjugation is emerging as a powerful complement to high-resolution crystallographic and spectroscopic methods in providing structural information on protein-nucleic acid complexes. Since the first report of attachment of the chemical nuclease 5-(iodoacetyl)-1,10 phenanthroline to Cys178 of the Escherichia coli catabolite gene activator protein (CAP, Ebright, R.H., et al. PNAS 87, 2882-86, 1990), photoactivable (Yang, S.W., and Nash, H.A. PNAS 91, 12183-87, 1994), fluorescent (Endrich, M.M., et al. J. Biol. Chem. 274, 5326-32, 1999), nucleolytic (Pan, C.Q., et al. Protein Sci. 4, 2279-88, 1995), and proteolytic (Hall, K.B., and Fox, R.O. Methods 18, 78-84, 1999) agents have been tethered to probe either component of nucleoprotein complexes. This strategy has recently been applied to study integrase (IN; Heuer, T.S., and Brown, P.O. Biochemistry 37, 6667-78, 1998) and reverse transcriptase (RT; Canard, B., et al. PNAS 94, 11279-84, 1988) of HIV via thiol tethering of the photo-crosslinker p-azidophenacyl to nucleic acid.

We have substituted Cys38 and Cys280 of wild-type and RNase H-deficient HIV-1 RT with Ser, and introduced a unique Cys at the extreme p66 C-terminus of these enzymes without compromising enzyme function. The resulting 'mono-Cys' RTs were site-specifically alkylated with p-azidophenacyl to determine the spatial proximity of template and primer nucleotides to the RNase H C-terminus in a variety of replication complexes (Rausch, J., et al. J. Biol. Chem. 275, 16015-22, 2000). More recently we have expanded this approach by attaching fluorophores to HIV-1 RT to examine, by single molecule FRET, its orientation when bound to diverse nucleic acid substrates. Further details can be found at http://home.ncifcrf.gov/hivdrp/Le_Grice.html.

A postdoctoral position is periodically available to extend this technology to a study of the conformationally distinct nucleic acid duplexes encountered by the retroviral polymerase during replication. Two approaches will be taken, namely (a) attachment of chemical nucleases to the retroviral polymerase for site-specific cleavage of the nucleic acid substrate and (b) attachment of chemical proteases to the nucleic acid substrate for site-specific proteolysis.

Candidates should have a strong background in chemistry or biochemistry. Please click on the button below, or send a cover letter, CV including bibliography, and contact information for three references to the following address:

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