SUNY at Albany
June 19-23, 2001
Three-Dimensional Structure Of The V3 Loop Of Thailand HIV Isolate
The principal neutralizing determinant (PND) of HIV-1 is located in the third hypervariable region (V3) of the envelope glycoprotein gp120. The V3 loop is typically 35 amino-acids long, and the 1st and 35th residues in the loop are invariant cysteines involved in a disulfide-bridge. Analysis of the V3 sequences has revealed that although certain position in the V3 loop are relatively well conserved, others vary considerably. Because an antibody recognizes a specific conformation of the antigen, the knoledge of three-dimensional structures of the V3 loops from a large number of HIV isolates is one of the foundations to understanding the specific interactions that govern PND-antibody complex formation.
In this study we determined the locally accurate spatial structure of the V3 loop of HIV isolate from Thailand and compared its structural parameters with the ones obtained earlier (1) for the V3 loop of the HIV isolate from Minnesota. The structure modeling was performed by an integrated _bottom-up_ approach (2) to computation and refinement of a probabilistic model, based on the use of NMR data, in conjunction with additional theoretical and empirical information. To build the model, the published experimental data (3) on the distance constraints and coupling constants were employed.
For the V3 loop of Thailand HIV isolate, the global structural properties were defined, the conformational states of individual amino acid residues determined, the secondary structure established, and the probable H-binding system proposed. As the result of the study, the following major conclusions are made: i) the V3 loop can be devided into the five regions which form the two adjacent beta-turns III-III [residues 3-9], the two extended segments [9-13 and 23-30], the triple beta-turn II-IV-IV [15- 21], and the right-handed alpha-helix [31-35]; ii) the three successive and overlapping beta-turns observed in the most probable viral immunodominant epitope [residues 15-21] form a compact loop which extends from the protein surface, possibly in the way that enhances the interaction of the antigen with an antibody; iii) a beta-turn conformation in the stretch Asp6-Asp7-Thr8, including the site of N- linked glycosylation [Asp6], is required for recognition of the tripeptide as a receptor by a glycosyl transferase; iv) in spite of the fact that there are conserved secondary structural elements inside the V3 loops from Thailand and Minnesota, the conformational differences between their local structures are found to be statistically significant.
The results obtained are discussed in connection with the data derived for the V3 loop of Thailand HIV isolate in the study (3).
Alexander M. Andrianov
Institute of Bioorganic Chemistry, Belarus Academy of Sciences, Kuprevich St., 5/2, 220141 Minsk,
Republic of Belarus