One of our major recent achievements has been the successful solution and refinement of the structure of the Lansing strain of poliovirus type 2 in complex with antiviral agent SCH48973 at 2.9 ? resolution (Lentz et al., Structure, 5:961-978, 1997) using data collected at CHESS. Since the structures of poliovirus 1 Mahoney and poliovirus 3 Sabin were previously solved by Dr. James Hogle, this has permitted a comparison of the structures of all serotypes of a picornavirus for the first time. The structure of poliovirus 2 Lansing has revealed a wealth of information about features such as capsid stability, host range specificity, antiviral agent binding, and poliovirus capsid assembly and disassembly. We have also been able to solve numerous additional important structures of HIV-1 RT using data collected at CHESS. These include structures of: 1) mutants of HIV-1 RT that are resistant to both nucleoside and nonnucleoside inhibitors; 2) HIV-1 RT complexed with nonnucleoside inhibitors from Janssen, Hoechst and NIH; and 3) a complex of HIV-1 RT with bound RNA/DNA. We have also made important preliminary progress in determining the structure of a ternary complex of HIV-1 RT with bound template-primer and AZT- and PMEA-triphosphate. The HIV-1 RT structural work has continued to spawn additional publications relating to drug resistance, polymerization mechanisms, and general polymerase structure and function (for detailed list see below). The structures of the Met184Ile (in complex with dsDNA), Lys103Asn (with and without bound inhibitors), and Tyr188Leu (with bound HBY 097) mutants of HIV-1 RT have been solved. This work is illuminating the structural basis of HIV-1 RT drug resistance for the first time, and the results from each of the studies point to diverse mechanisms for how the enzyme loses sensitivity to important drugs used in the treatment of AIDS. Highlights include: 1) a large movement of the template-primer in the Met184Ile mutant relative to its position in the wild-type RT/DNA complex and a structural explanation for high-level resistance against 3TC; and 2) a novel mechanism of drug resistance for the Lys103Asn mutant that is resistant to nonnucleoside inhibitors: the unbound enzyme has a rearranged structure of the inhibitor-binding region whereas the bound complexes are very similar to the wild-type complexes. The outstanding leadership and facilities at CHESS have made it possible for us to carry out these determinations which would otherwise have been unfeasible.
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