5gds: Difference between revisions
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==Overview== | ==Overview== | ||
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 alpha-thrombin and hirunorm V, a, 26-residue polypeptide containing non-natural amino acids, determined at, 2.1 A 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 (Ki 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 Chg1"-Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin, main-chain residues Ser214-Gly219. The Chg1" side chain fills the S2, subsite, Val2" is located at the entrance of S1, whereas 2-Nal3" 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-termninal tail and related compounds. The linker polypeptide segment, connecting hirunorm V N-and 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 alpha-thrombin and hirunorm V, a, 26-residue polypeptide containing non-natural amino acids, determined at, 2.1 A 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 (Ki 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 Chg1"-Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin, main-chain residues Ser214-Gly219. The Chg1" side chain fills the S2, subsite, Val2" is located at the entrance of S1, whereas 2-Nal3" 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-termninal tail and related compounds. The linker polypeptide segment, connecting hirunorm V N-and 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. | ||
==Disease== | |||
Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: thrombin synthetic inhibitors]] | [[Category: thrombin synthetic inhibitors]] | ||
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Revision as of 00:45, 13 November 2007
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HIRUNORMS ARE TRUE HIRUDIN MIMETICS. THE CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN:HIRUNORM V COMPLEX
OverviewOverview
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 alpha-thrombin and hirunorm V, a, 26-residue polypeptide containing non-natural amino acids, determined at, 2.1 A 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 (Ki 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 Chg1"-Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin, main-chain residues Ser214-Gly219. The Chg1" side chain fills the S2, subsite, Val2" is located at the entrance of S1, whereas 2-Nal3" 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-termninal tail and related compounds. The linker polypeptide segment, connecting hirunorm V N-and 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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
5GDS is a Single protein structure of sequence from Homo sapiens with NAG as ligand. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: CAT. Full crystallographic information is available from OCA.
ReferenceReference
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex., De Simone G, Lombardi A, Galdiero S, Nastri F, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V, Protein Sci. 1998 Feb;7(2):243-53. PMID:9521099
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OCA- Pages with broken file links
- Homo sapiens
- Single protein
- Thrombin
- Bolognesi, M.
- Galdiero, S.
- Lombardi, A.
- Morte, R.Della.
- Nastri, F.
- Pavone, V.
- Pedone, C.
- Simone, G.De.
- Staiano, N.
- NAG
- Antithrombotics
- Blood coagulation
- Complex (serine protease/inhibitor)
- Hirudin-like binding mode
- Hirunorms
- Thrombin synthetic inhibitors