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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

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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

Fengler, A.; Brandt, W.; Development and Validation of Homology Models of Human Cathepsins K, S, H, and F Adv. Exp. Med. Biol. 477, 255-260, (2002) ISBN: 978-0-306-46826-1 DOI: 10.1007/0-306-46826-3_27

Models of the tertiary structures of cathepsins K, S, H, and F were constructed by using homology protein modelling methods and refinements by interactive graphics and energy minimisation. The predicted structures yield information regarding their substrate binding sites and indicate the residues surrounding these sites. The ligandbinding sites were characterised and compared with each other by means of calculated molecular electrostatic surface potentials. This will allow designing and development of new ligands specific for these cathepsins in future investigations.
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

Fengler, A.; Brandt, W.; Development and Validation of a Homology Model of Human Cathepsin H Including the Mini-Chain J. Mol. Model. 5, 177-188, (1999) DOI: 10.1007/s008940050117

Cathepsin H is involved in intracellular protein degradation and is implicated in a variety of physiological processes such as proenzyme activation, enzyme inactivation, hormone maturation, tissue remodeling, and bone matrix resorption. A model of the tertiary structure of the human lysosomal cysteine protease cathepsin H was constructed. The protein structure was built from its amino acid sequence and its homology to papain, actinidin, and cathepsin L for which crystallographic co-ordinates are available. The model was generated using the COMPOSER module of SYBYL.The position and interaction behavior of the so called mini-chain, the octapeptide EPQNCSAT, to the active-site cleft of cathepsin H could be determined by docking studies. Refinement was achieved through interactive visual and algorithmic analysis and minimization with the TRIPOS force field. The model was found to correlate with observed empirical data regarding ligand specificity. The model defines possible steric, hydrophobic, and electrostatic interactions. We anticipate that the model will serve as a tool to understand substrate specificity and may be used for the development of new specific ligands.
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.; Brandt, W.; Three-dimensional structures of the cysteine proteases cathepsins K and S deduced by knowledge-based modelling and active site characteristics Protein Eng. Des. Sel. 11, 1007-1013, (1998) DOI: 10.1093/protein/11.11.1007

Human cathepsins K and S are recently identified proteins with high primary sequence homology to members of papain superfamily, including cathepsins B, L, H and papain. Models of the tertiary structures of cathepsins K and S and their complexes with a specific substrate and inhibitor were constructed and compared with the recently determined X-ray structure of cathepsin K. A major problem in the determination of the three-dimensional structure of proteins concerns the quality of the structural models obtained from the interpretation of experimental data. The framework of the tertiary structures of cathepsins K and S consisted of structurally conserved regions from the tertiary structure of the papain superfamily and the variable regions were constructed with fragments of other proteins from the protein data base. Based on docking studies the non-bonded interaction energies of ligands with the cathepsins were estimated. These energies correlate with experimentally determined substrate and inhibitory potency.
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)

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