zur Suche springenzur Navigation springenzum Inhalt springen

Sortieren nach: Erscheinungsjahr Typ der Publikation

Zeige Ergebnisse 1 bis 10 von 11.

Bücher und Buchkapitel

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.
Publikation

Lorey, S.; Stöckel-Maschek, A.; Faust, J.; Brandt, W.; Stiebitz, B.; Gorrell, M. D.; Kähne, T.; Mrestani-Klaus, C.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N-terminus of HIV-1 Tat indicate at least two inhibitor binding sites Eur. J. Biochem. 270, 2147-2156, (2003) DOI: 10.1046/j.1432-1033.2003.03568.x

Dipeptidyl peptidase IV (DP IV, CD26) plays an essential role in the activation and proliferation of lymphocytes, which is shown by the immunosuppressive effects of synthetic DP IV inhibitors. Similarly, both human immunodeficiency virus‐1 (HIV‐1) Tat protein and the N‐terminal peptide Tat(1–9) inhibit DP IV activity and T cell proliferation. Therefore, the N‐terminal amino acid sequence of HIV‐1 Tat is important for the inhibition of DP IV. Recently, we characterized the thromboxane A2 receptor peptide TXA2‐R(1–9), bearing the N‐terminal MWP sequence motif, as a potent DP IV inhibitor possibly playing a functional role during antigen presentation by inhibiting T cell‐expressed DP IV [Wrenger, S., Faust, J., Mrestani‐Klaus, C., Fengler, A., Stöckel‐Maschek, A., Lorey, S., Kähne, T., Brandt, W., Neubert, K., Ansorge, S. & Reinhold, D. (2000) J. Biol. Chem. 275 , 22180–22186]. Here, we demonstrate that amino acid substitutions at different positions of Tat(1–9) can result in a change of the inhibition type. Certain Tat(1–9)‐related peptides are found to be competitive, and others linear mixed‐type or parabolic mixed‐type inhibitors indicating different inhibitor binding sites on DP IV, at the active site and out of the active site. The parabolic mixed‐type mechanism, attributed to both non‐mutually exclusive inhibitor binding sites of the enzyme, is described in detail. From the kinetic investigations and molecular modeling experiments, possible interactions of the oligopeptides with specified amino acids of DP IV are suggested. These findings give new insights for the development of more potent and specific peptide‐based DP IV inhibitors. Such inhibitors could be useful for the treatment of autoimmune and inflammatory diseases.
Bücher und Buchkapitel

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

0
Bücher und Buchkapitel

Wrenger, S.; Reinhold, D.; Faust, J.; Mrestani-Klaus, C.; Brandt, W.; Fengler, A.; Neubert, K.; Ansorge, S.; Effects of Nonapeptides Derived From the N-terminal Structure of Human Immunodeficiency Virus-1 (HIV-1) Tat on Suppression of CD26-Dependent T Cell Growth Adv. Exp. Med. Biol. 477, 161-165, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_18

The human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and exerts immunosuppressive effects. Interestingly, Tat inhibits dipeptidyl peptidase IV (DP IV) activity of the T cellactivation marker CD26. The short N-terminal nonapeptideTat(l-9), MDPVDPNIE, also inhibits DP IV activity and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells (PBMC). Here, we present the influence of amino acid exchanges in the first three positions of Tat(l-9). For instance, the replacement of D2 of Tat(l-9) by G or K generated peptides, which inhibit DP IV-catalyzed IL-2(1-12) cleavage nearly threefold stronger. Similar effects were observed on the suppression of DNA synthesis of Tetanus toxoid-stimulated PBMC. This correlation suggests that Tat(l-9)-deduced peptides mediate antiproliferative effects at least in part via specific DP IV interactions and supports the hypothesis that CD26 plays a key role in the regulation of lymphocyte growth.
Bücher und Buchkapitel

Faust, J.; Wrenger, S.; Reinhold, D.; Kähne, T.; Lorey, S.; Stöckel-Maschek, A.; Brandt, W.; Mrestani-Klaus, C.; Stiebitz, B.; Fuchs, P.; Ansorge, S.; Neubert, K.; Down regulation of T-cell activation by synthetic dipeptidyl peptidase IV inhibitors with the N.terminal MXP sequence (Bendetti, E. & Predone, C., eds.). 750-751, (2002)

0
Publikation

Wrenger, S.; Faust, J.; Mrestani-Klaus, C.; Fengler, A.; Stöckel-Maschek, A.; Lorey, S.; Kähne, T.; Brandt, W.; Neubert, K.; Ansorge, S.; Reinhold, D.; Down-regulation of T Cell Activation following Inhibition of Dipeptidyl Peptidase IV/CD26 by the N-terminal Part of the Thromboxane A2 Receptor J. Biol. Chem. 275, 22180-22186, (2000) DOI: 10.1074/jbc.M002338200

Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1–9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1–9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp2-Tat(1–9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1–9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1–9) induces the production of the immunosuppressive cytokine transforming growth factor-β1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.
Bücher und Buchkapitel

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.
Publikation

Mrestani-Klaus, C.; Fengler, A.; Brandt, W.; Faust, J.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; 1H NMR conformational study on n-terminal nonapeptide sequences of HIV-1 Tat protein: a contribution to structure–activity relationships J. Pept. Sci. 4, 400-410, (1998) DOI: 10.1002/(SICI)1099-1387(199809)4:6<400::AID-PSC162>3.0.CO;2-G

On the basis of our recent results, the N‐terminal sequence of HIV‐1 Tat protein as a natural competitive inhibitor of dipeptidyl peptidase IV (DP IV) is supposed to interact directly with the active site of DP IV hence mediating its immunosuppressive effects via specific DP IV interactions. Of special interest is the finding that amino acid substitutions of the Tat(1–9) peptide (MDPVDPNIE) in position 5 with S‐isoleucine and in position 6 with S‐leucine led to peptides with strongly reduced inhibitory activity suggesting differences in the solution conformation of the three analogues. Therefore, 1H NMR techniques in conjunction with molecular modelling have been used here to determine the solution structure of Tat(1–9), I5‐Tat(1–9) and L6‐Tat(1–9) and to examine the influence of amino acid exchanges on structural features of these peptides. The defined structures revealed differences in the conformations what might be the reason for different interactions of these Tat(1–9) analogues with certain amino acids of the active site of DP IV.
Publikation

Fengler, A.; Mrestani-Klaus, C.; Reinhold, D.; Wrenger, S.; Ansorge, S.; Faust, J.; Neubert, K.; Brandt, W.; Determination of the Solution Conformation of HIV-1 Tat(1–9) Peptides by Means of Molecular Dynamics Simulations Considering NMR Data and Docking Studies into an Active Site Model of DP IV J. Mol. Model. 4, 200-210, (1998) DOI: 10.1007/s0089480040200

The human immunodeficiency virus 1 Tat protein suppresses antigen-, anti-CD3-and mitogen-induced activation of human T cells when added to T cell cultures. This activity is important for the development of AIDS because lymphocytes from HIV-infected individuals exhibit a similar antigen-specific dysfunction. Moreover, Tat was found to interact with dipeptidyl peptidase IV (DP IV). To find out the amino acid sequence important for the inhibition of the DP IV enzymatic activity we investigated N-terminal Tat(1–9) peptide analogues with amino acid substitutions in different positions. Interestingly, the exchange of Pro6 with Leu and Asp5 with Ile strongly diminished the DP IV inhibition by Tat(1–9). Based on data derived from one-and two-dimensional 1H NMR investigations the solution conformations of the three nonapeptides in water were determined by means of molecular dynamics simulations. These conformations were used for studies of the docking behavior of the peptides into a model of the active site of DP IV. The results suggest that several attractive interactions between the native Tat(1–9) and DP IV lead to a stable complex and that the reduced affinity of both L6-Tat(1–9) and I5-Tat(1–9) derivatives might be caused by conformational alterations in comparison to the parent peptide.
Bücher und Buchkapitel

Faust, J.; Mrestani-Klaus, C.; Fengler, A.; Brandt, W.; Wrenger, S.; Reinhold, D.; Ansorge, S.; Neubert, K.; HIV-1 Tat(1-9): Structure and Activity Studies 580-581, (1998)

0
IPB Mainnav Search