Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex(520 views) De Simone G, Lombardi A, Galdiero S, Nastri F, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1998 Feb; 7(2): 243-253.
Keywords: Antithrombotics, Hirudin-Like Binding Mode, Hirunorms, Thrombin Synthetic Inhibitors, X-Ray Crystal Structure, Thrombin Inhibitor, Unclassified Drug, Article, Blood Clotting, Carboxy Terminal Sequence, Complex Formation, Crystallography, Human, Human Cell, Molecular Biology, Priority Journal, Protein Binding, Protein Interaction, Protein Structure, Antithrombins, Molecular Mimicry, Oligopeptides, Protein Conformation, Solvents,
Affiliations: Ctro. Interuniversitario Ric. su P., Ctro. Stud. Biocristallografia - CNR, University of Napoli Federico II, via Mezzocannone 4, 80134 Napoli, Italy
Dipto. Biochim. Biotecnologie M., University of Napoli Federico II, via Pansini 5, 80129 Napoli, Italy
Dipto. di Genetica e Microbiologia, University of Pavia, Via Abbiategrasso 207, 27100 Pavia, Italy
Advanced Biotechnology Center, Department of Physics, University of Genova, Largo Rosanna Benzi, 10, 16132 Genova, Italy
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Iwanowicz, E. J., Lau, W. F., Lin, J., Roberts, D. G. M., Seiler, S. M., Retro-binding tripeptide thrombin active-site inhibitors: Discovery synthesis and molecular modeling (1994) J Med Chem, 37, pp. 2122-2124
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Krstenansky, J. L., Broersma, R. J., Owen, T. J., Payne, M. H., Yates, M. T., Mao, S. J., Development of MDL 28050 a small antithrombin agent based on a functional domain of the leech protein hirudin (1990) Thromb Haemostasis, 63, pp. 208-214
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Maraganore, J. M., Bourdon, P., Jablonski, J., Ramachandran, K. L., Fenton II, J. W., Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin (1990) Biochemistry, 29, pp. 7095-7101
Maryanoff, B. E., Qiu, X., Padmanabhan, K. P., Tulinsky, A., Almond Jr., H. R., Andrade-Gordon, P., Greco, M. N., Fusetani, N., Molecular basis for the inhibition of human -thrombin by the macrocyclic peptide cyclotheonamide A (1993) Proc Natl Acad Sci USA, 90, pp. 8048-8052
Mathews, I. I., Padmanabhan, K. P., Ganesh, V., Tulinsky, A., Isshii, M., Chen, J., Turck, C. W., Coughlin, S. R., Crystallographic structures of thrombin complexed with thrombin receptor peptides: Existence of expected and novel binding modes (1994) Biochemistry, 33, pp. 3266-3279
Rydel, T. J., Ravichandran, K. G., Tulinsky, A., Bode, W., Huber, R., Roitsch, C., Fenton, J. W., The structure of a complex of recombinant hirudin and human -thrombin (1990) Science, 249, pp. 277-280
Rydel, T. J., Tulinsky, A., Bode, W., Huber, R., Refined structure of the hirudin-thrombin complex (1991) J Mol Biol, 221, pp. 583-601
Salemme, F. R., Spurlino, J., Bone, R., Serendipity meets precision: The integration of structure-based drug design and combinatorial chemistry for efficient drug discovery (1997) Structure, 5, pp. 319-324
Stubbs, M. T., Bode, W., A player of many parts: The spotlight falls on thrombin's structure (1993) Thromb Res, 69, pp. 1-58
Stubbs, M. T., Oschkinat, H., Mayr, I., Huber, R., Angliker, H., Stone, S. R., Bode, W., The interaction of thrombin with fibrinogen. A structural basis for its specificity (1992) Eur J Biochem, 206, pp. 187-195
Stura, E. A., Wilson, I. A., Seeing techniques (1992) Crystallization of Nucleic Acids and Proteins: A Practical Approach, pp. 99-126. , Ducruix A, Gieg R, eds. Oxford, UK: Oxford University Press
Tollefsen, D. M., Feagler, J. R., Majerus, P. W., The binding of thrombin to the surface of human platelets (1974) J Biol Chem, 249, pp. 2646-2651
Vu, T. K. H., Wheaton, V. I., Hung, D. T., Charo, I., Coughlin, S. R., Domains specifying thrombin receptor interaction (1991) Nature, 353, pp. 674-677
Wu, T. P., Yee, V., Tulinsky, A., Chrusciel, R. A., Nakanashi, H., Shen, R., Priebe, C., Kahn, M., The structure of a designed peptidomimetic inhibitor complex of -thrombin (1993) Protein Eng, 6, pp. 471-478
Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex
A novel class of synthetic, multisite-directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human a-thrombin and hirunorm V, a 26-residue polypeptide containing non-natural amino acids, determined at 2. 1 Angstrom resolution and refined to an R-factor of 0. 176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (K-i is in the picomolar range) and the strong selectivity of hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with the thrombin active site in a nonsubstrate mode; at the same time, this inhibitor specifically binds through the C-terminal segment to the fibrinogen recognition exosite, The backbone of the N-terminal tetrapeptide Chg (1) "-Val (2) "-2-Nal (3) "-Thr (4) " (Chg, cyclohexyl-glycine; 2-Nal, beta- (2-naphthyl) -alanine) forms a short beta-strand parallel to thrombin main-chain residues Ser (214) -Gly (219). The Chg (1) " side chain fills the S2 subsite, Val (2) " is located at the entrance of S1, whereas 2-Nal (3) " side chain occupies the aryl-binding site. Such backbone orientation is very close to that observed for the N-terminal residues of hirudin, and it is similar to that of the synthetic retro-binding peptide BMS-183507, but it is opposite to the proposed binding mode of fibrinogen and of small synthetic substrates. Hirunorm V C-terminal segment binds to the fibrinogen recognition exosite, similarly to what observed for hirudin C-terminal tail and related compounds. The linker polypeptide segment connecting hirunorm V Nand C-terminal regions is not observable in the electron density maps. The crystallographic analysis proves the correctness of the design and it provides a compelling proof on the interaction mechanism for this novel class of high potency multisite-directed synthetic thrombin inhibitors
Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex
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Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex