Crystal Structures of HIV-1 Tat-derived Nonapeptides Tat-(1–9) and Trp2-Tat-(1–9) Bound to the Active Site of Dipeptidyl-peptidase IV (CD26)

• Published in: The Journal of biological chemistry Vol. 280; no. 15; pp. 14911 - 14917
• Main Authors: Weihofen, Wilhelm Andreas, Liu, Jianguo, Reutter, Werner, Saenger, Wolfram, Fan, Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Deaminase - chemistry; Binding Sites; Crystallography, X-Ray; Dipeptidyl Peptidase 4 - chemistry; Electrons; Gene Products, tat - chemistry; Glycoproteins - chemistry; HIV-1 - metabolism; Humans; Immunosuppressive Agents - pharmacology; Kinetics; Methionine - chemistry; Models, Molecular; Mutation; Peptide Fragments - chemistry; Peptides - chemistry; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Substrate Specificity; tat Gene Products, Human Immunodeficiency Virus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M413400200

CD26 or dipeptidyl-peptidase IV (DPPIV) is engaged in immune functions by co-stimulatory effects on activation and proliferation of T lymphocytes, binding to adenosine deaminase, and regulation of various chemokines and cytokines. DPPIV peptidase activity is inhibited by both Tat protein from human immunodeficiency virus (HIV)-1 and its N-terminal nonapeptide Tat-(1–9) with amino acid sequence MDPVDPNIE, suggesting that DPPIV mediates immunosuppressive effects of Tat protein. The 2.0- and 3.15-Å resolution crystal structures of the binary complex between human DPPIV and nonapeptide Tat-(1–9) and the ternary complex between the variant MWPVDPNIE, called Trp2-Tat-(1–9), and DPPIV bound to adenosine deaminase show that Tat-(1–9) and Trp2-Tat-(1–9) are located in the active site of DPPIV. The interaction pattern of DPPIV with Trp2-Tat-(1–9) is tighter than that with Tat-(1–9), in agreement with inhibition constants (Ki) of 2 × 10–6 and 250 × 10–6m, respectively. Both peptides cannot be cleaved by DPPIV because the binding pockets of the N-terminal 2 residues are interchanged compared with natural substrates: the N-terminal methionine occupies the hydrophobic S1 pocket of DPPIV that normally accounts for substrate specificity by binding the penultimate residue. Because the N-terminal sequence of the thromboxane A2 receptor resembles the Trp2-Tat-(1–9) peptide, a possible interaction with DPPIV is postulated.