Insights into DNA polymerization mechanism and drug design from structural studies of the aids virus reverse transcriptase

In a collaboration with the laboratory of Dr. Stephen Hughes at the ABL-Frederick Cancer Research and Development Center we have been pursuing structural studies of HIV-1 reverse transcriptase (RT). Using the techniques of X-ray crystallography, we have obtained structures of HIV-1 RT with a bound nucleic acid templateprimer (Jacobo-Molina et ai, PNAS 90:6320-6324, 1993), with bound non-nucleoside inhibitors (Ding et al., Structure 3:365379, 1995; Ding et al, Nat. Struct. Biol. 2:407-415, 1995) and without bound ligands (Hsiou et al, in preparation). These results, together with structures obtained by several other laboratories, have provided insights into the conformational flexibility of HIV-1 RT, as well as mechanisms of polymerization, inhibition, and drug resistance. Implications for structure-based drue design and for therapeutic strategies will be discussed.