THE STRUCTURE OF HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH 9-CHLORO-TIBO - LESSONS FOR INHIBITOR DESIGN

Background: HIV reverse transcriptase (RT) is a key target of anti-AID S therapies. Structural studies of HIV-1 RT, unliganded and complexed with different nonnucleoside inhibitors (NNIs), have pointed to a comm on mode of binding and inactivation through distortion of the polymera se catalytic site by NNIs containing two hinged rings. The mode of bin ding of the TIBO family of inhibitors is of interest because these com pounds do not fit the two-hinged-ring model. Results: The structure of HIV-1 RT complexed with 9-chloro-TIBO (R82913) has been determined at 2.6 Angstrom resolution. As reported for the lower resolution analysi s of another TIBO compound, this inhibitor binds at the same site as o ther NNIs, but our higher resolution study reveals the Cl-TIBO is dist orted from the conformation seen in crystals of the inhibitor alone. T his allows Cl-TIBO to mimic the binding of NNIs containing two hinged rings. Inhibitor-protein interactions are again predominantly hydropho bic and the protein conformation corresponds to that seen in complexes with other tight-binding NNIs. Conclusions: Although Cl-TIBO is chemi cally very different from other NNIs, it achieves remarkable spatial e quivalence and shape complementarity with other NNIs on binding to RT. Comparison of the different RT-NNI complexes suggests modifications t o the TIBO group of inhibitors which might enhance their binding and h ence, potentially, their therapeutic efficacy.