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).
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-A resolution crystal structures of the binary complex between human DPPIV and nonapeptide Tat-(1-9) and the ternary complex between the variant MWPVDPNIE, called Trp(2)-Tat-(1-9), and DPPIV bound to adenosine deaminase show that Tat-(1-9) and Trp(2)-Tat-(1-9) are located in the active site of DPPIV. The interaction pattern of DPPIV with Trp(2)-Tat-(1-9) is tighter than that with Tat-(1-9), in agreement with inhibition constants (K(i)) of 2 x 10(-6) and 250 x 10(-6) m, 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 Trp(2)-Tat-(1-9) peptide, a possible interaction with DPPIV is postulated.
Weihofen
Wilhelm Andreas
WA
Institut für Chemie/Kristallographie, Freie Universität Berlin, Takustrasse 6, D-14195 Berlin, Germany.
Liu
Jianguo
J
Reutter
Werner
W
Saenger
Wolfram
W
Fan
Hua
H
D000243:Adenosine Deaminase / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D004583:Electrons; D015696:Gene Products, tat / Q000737:chemistry*; D006023:Glycoproteins / Q000737:chemistry*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007700:Kinetics; D008715:Methionine / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D010455:Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; C415751:tat peptide (1-9), Human immunodeficiency virus 1; D008715:Methionine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase