Title : 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) - Weihofen_2005_J.Biol.Chem_280_14911 |
Author(s) : Weihofen WA , Liu J , Reutter W , Saenger W , Fan H |
Ref : Journal of Biological Chemistry , 280 :14911 , 2005 |
Abstract :
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. |
PubMedSearch : Weihofen_2005_J.Biol.Chem_280_14911 |
PubMedID: 15695814 |
Gene_locus related to this paper: human-DPP4 |
Inhibitor | Trp2-Tat-(1-9) Tat-(1-9) |
Gene_locus | human-DPP4 |
Structure | 2BGN 2BGR |
Weihofen WA, Liu J, Reutter W, Saenger W, Fan H (2005)
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)
Journal of Biological Chemistry
280 :14911
Weihofen WA, Liu J, Reutter W, Saenger W, Fan H (2005)
Journal of Biological Chemistry
280 :14911