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Books and chapters

Mrestani-Klaus, C.; Brandt, W.; Faust, J.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; New Results on the Conformations of Potent DP IV (CD26) Inhibitors bearing the N-terminal MWP Structural Motif Adv. Exp. Med. Biol. 524, 65-68, (2004) DOI: 10.1007/0-306-47920-6_7

Conformational analysis by NMR spectroscopy and molecular modeling revealed a left-handed PPII helix-like structure for Trp2-Tat(1–9) (cis and trans) and an even more flexible structure for TXA2-R(1–9).PPII helices form a well-defined structural class comparable with the other structures defined in proteins and are characterized by exposed, mobile structures with 4–8 residues, mostly found on the protein surface. Polyproline II helices are mainly identified by their torsion angles of φ∼−75° and Ψ∼145−. They do not form regular interchain hydrogen bonds, but are hydrogen bonded with water molecules. PPII helices have a strong preference for the amino acid proline, although it is not necessarily present. These features were also reported for the parent peptide Tat(1–9)4 as well as for the well known DP IV substrates neuropeptide Y and pancreatic polypeptide5 suggesting that PPII-like helical structures represent a favored structural class for the interaction with DP IV.Thus, the considerable enhancement of the inhibition capacity of both Trp2-Tat(1–9) and TXA2-R(1–9) compared to the moderate inhibitor Tat(1–9)2, Ki=2.68±0.01 10−4 M, can only be due to tryptophan in the second position suggesting that its side chain is favored to exhibit attractive hydrophobic interactions with DP IV compared with aspartic acid.On the other hand, we could show recently that Tat(1–9) and its analogues as well as TXA2-R(1–9) inhibit DP IV according to different inhibition mechanisms (Lorey et al., manuscript submitted). One possible explanation for these findings might be enzyme-ligand interactions relying on multiple weak binding sites as described for PPII helices5 rather than specific lock and key binding. Certainly, only an X-ray structure of DP IV would help to understand the interaction of DP IV with inhibitors.
Books and chapters

Bühling, F.; Fengler, A.; Brandt, W.; Welte, T.; Ansorge, S.; Nagler, D. K.; Review: Novel Cysteine Proteases of the Papain Family Adv. Exp. Med. Biol. 477, 241-254, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_26

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Books and chapters

Mrestani-Klaus, C.; Fengler, A.; Faust, J.; Brandt, W.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; N-Terminal HIV-1 Tat Nonapeptides as Inhibitors of Dipeptidyl Peptidase IV. Conformational Characterization Adv. Exp. Med. Biol. 477, 125-129, (2000) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_13

Compared to the N-terminal nonapeptide of the HIV-1 Tat protein as inhibitor of activity of DP IV which is supposed to mediate the immunosuppressive effects of HIV-1 Tat, the Ile5 and Leu6 analogues showed strongly reduced inhibitory activity. Interestingly, replacement of Asp2 with Gly or Lys led to compounds with considerably enhanced inhibition. Therefore, we have applied 1H NMR spectroscopy and restrained molecular dynamics calculations to elucidate the molecular conformation of a series of Tat nonapeptides. Conformational backbone differences of these peptides as well as the nature and the arrangement of the side chains per se at significant positions preventing effective binding to DP IV might explain their different inhibitory activity on DP IV.
Publications

Wrenger, S.; Hoffmann, T.; Faust, J.; Mrestani-Klaus, C.; Brandt, W.; Neubert, K.; Kraft, M.; Olek, S.; Frank, R.; Ansorge, S.; Reinhold, D.; The N-terminal Structure of HIV-1 Tat Is Required for Suppression of CD26-dependent T Cell Growth J. Biol. Chem. 272, 30283-30288, (1997) DOI: 10.1074/jbc.272.48.30283

Evidence exists that the human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and is involved in the immunosuppression of non-HIV-1-infected T cells of acquired immunodeficiency syndrome (AIDS) patients. The mechanism of this immunosuppressive activity of Tat has been controversially discussed. Interestingly, Tat binds to the T cell activation marker CD26, which has been shown to play a key role in the regulation of growth of lymphocytes and to inhibit its dipeptidyl peptidase IV (DP IV) activity. Here we show that the N-terminal nonapeptide MDPVDPNIE of Tat is a competitive inhibitor of DP IV and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells. Amino acid exchanges at positions 5 and 6 strongly weaken these effects.1H nuclear magnetic resonance and molecular dynamics simulations of Tat(1–9), I5-Tat(1–9), and L6-Tat(1–9) suggest a similar backbone conformation for Tat(1–9) and L6-Tat(1–9). The solution conformation of I5-Tat(1–9) considerably differs from the other two. However, Tat(1–9) fits into our previously proposed active site model of DP IV in contrast to I5-Tat(1–9) and L6-Tat(1–9). Conformational alterations with regard to the parent peptide and spatial hindrances between these both compounds and DP IV can explain the loss of inhibitory activity. Our data suggest that the N-terminal residues of HIV-1 Tat do interact directly with the active site of DP IV and that DP IV does mediate Tat’s immunosuppressive effects.
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