Structural model of the HIV-1 Tat(46-58)-TAR complex.

The trans-activator protein (Tat) of human immunodeficiency virus type 1 (HIV-1) binds to an uridine-rich bulge of an RNA target (TAR; trans-activation responsive element) predominantly via its basic sequence domain. The structure of the Tat(46-58)-TAR complex has been determined by a novel modeling approach relying on structural information about one crucial arginine residue and crosslink data. The strategy described here solely uses this experimental data without additional "modeling" assumptions about the structure of the complex in order to avoid human bias. Model building was performed in a fashion similar to structure calculations from nuclear magnetic resonance (NMR)-spectroscopic data using restrained molecular dynamics. The resulting set of structures of Tat(46-58) in its complex with TAR reveals that all models have converged to a common fold, showing a backbone root mean square deviation (RMSD) of 1.36A. Analysis of the calculated structures suggests that HIV-I Tat forms a hairpin loop in its complex with TAR that shares striking similarity to the hairpin formed by the structure of the bovine immunodeficiency virus Tat protein after TAR binding as determined by NMR studies. The outlined approach is not limited to the Tat-TAR complex modeling, but is also applicable to all molecular complexes with sufficient biochemical and biophysical data available.