Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex (898 views)
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1998 Feb; 7(2): 243-253.
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Paper type: Journal Article,
Impact factor: 4.44, 5-year impact factor: 3.602
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-0031890648&partnerID=40&md5=d81bc6e4a30626b70c66302ad4e6e62f
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
References:
Not available.
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1998 Feb; 7(2): 243-253.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 4.44, 5-year impact factor: 3.602
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-0031890648&partnerID=40&md5=d81bc6e4a30626b70c66302ad4e6e62f
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
References:
Not available.
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
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
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View Export to BibTeX Export to EndNote
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Impact Factor: 2.478
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View Export to BibTeX Export to EndNote
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Impact Factor: 4.457
View Export to BibTeX Export to EndNote
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Impact Factor: 2.331
View Export to BibTeX Export to EndNote
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Biol Chem Biological Chemistry (ISSN: 1431-6730, 1437-4315), 1998 Sep; 379(8-9): 987-1006.
Impact Factor: 2.636
View Export to BibTeX Export to EndNote
Pavone V, Lombardi A, Saviano M, Di Blasio B, Nastri F, Fattorusso R, Zaccaro L, Maglio O, Yamada T, Omote Y
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Impact Factor: 2.425
View Export to BibTeX Export to EndNote
10 Records (10 excluding Abstracts).
Total impact factor: 30.643 (30.643 excluding Abstracts).
Total 5 year impact factor: 29.672 (29.672 excluding Abstracts).
Total impact factor: 30.643 (30.643 excluding Abstracts).
Total 5 year impact factor: 29.672 (29.672 excluding Abstracts).
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