THE STRUCTURE OF UNLIGANDED REVERSE-TRANSCRIPTASE FROM THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

The crystal structure of the reverse transcriptase (RT) from the type 1 human immunodeficiency virus has been determined at 3.2-Angstrom res olution. Comparison with complexes between RT and the polymerase inhib itor Nevirapine [Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P . A. and Steitz, T. A. (1992) Science 256, 1783-1790] and between RT a nd an oligonucleotide [Jacobo-Molina, A., Ding, J., Nanni, R., Clark, A. D., Lu, X., Tantillo, C., Williams, R. L., Kamer, G., Ferris, A. L. , Clark, P., Hizi, A., Hughes, S. H. and Arnold, E. (1993) Proc. Natl. Acad. Sci. USA 90, 6320-6324] reveals changes associated with ligand binding. The enzyme is a heterodimer (p66/p51), with domains labeled ' 'fingers,'' ''thumb,'' ''palm,'' and ''connection'' in both subunits, and a ribonuclease H domain in the larger subunit only. The most strik ing difference between RT and both complex structures is the change in orientation of the p66 thumb (approximate to 33 degrees rotation). Sm aller shifts relative to the core of the molecule were also found in o ther domains, including the p66 fingers and palm, which contain the po lymerase active site. Within the polymerase catalytic region itself, t here are no rearrangements between RT and the RT/DNA complex. In RT/Ne virapine, the drug binds in the p66 palm near the polymerase active si te, a region that is well-packed hydrophobic core in the unliganded en zyme. Room for the drug is provided by movement of a small beta-sheet within the palm domain of the Nevirapine complex. The rearrangement wi thin the palm and thumb, as well as domain shifts relative to the enzy me core, may prevent correct placement of the oligonucleotide substrat e when the drug is bound.