1hbt
From Proteopedia
(New page: 200px<br /> <applet load="1hbt" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hbt, resolution 2.0Å" /> '''HUMAN ALPHA-THROMBIN...) |
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| - | [[Image:1hbt.gif|left|200px]]<br /> | + | [[Image:1hbt.gif|left|200px]]<br /><applet load="1hbt" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1hbt" size=" | + | |
caption="1hbt, resolution 2.0Å" /> | caption="1hbt, resolution 2.0Å" /> | ||
'''HUMAN ALPHA-THROMBIN COMPLEXED WITH A PEPTIDYL PYRIDINIUM METHYL KETONE CONTAINING BIVALENT INHIBITOR'''<br /> | '''HUMAN ALPHA-THROMBIN COMPLEXED WITH A PEPTIDYL PYRIDINIUM METHYL KETONE CONTAINING BIVALENT INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The crystal structure of a complex between a bivalent peptidyl pyridinium | + | The crystal structure of a complex between a bivalent peptidyl pyridinium methyl ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp- Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal, active-site-directed portion of the inhibitor is linked to the fibrinogen recognition exosite binding portion by a tetraglycine segment. The strong electron-withdrawing effect provided by the permanent positive charge on the pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a covalent P596-thrombin complex is observed. The electron density surrounding the active site portion and the pyridinium of the inhibitor is very well defined, clearly showing the existence of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of the inhibitor. The decreased binding ability of thrombin inhibitors containing N-terminal acetylation is discussed as is the effect of replacing the P3 (D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the remainder of the inhibitor is generally well defined, the exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS) |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1HBT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CHX as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Full crystallographic information is available from [http:// | + | 1HBT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CHX:'>CHX</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HBT OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Thrombin]] | [[Category: Thrombin]] | ||
[[Category: Cygler, M.]] | [[Category: Cygler, M.]] | ||
| - | [[Category: Rehse, P | + | [[Category: Rehse, P H.]] |
[[Category: CHX]] | [[Category: CHX]] | ||
[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:59:32 2008'' |
Revision as of 10:59, 21 February 2008
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HUMAN ALPHA-THROMBIN COMPLEXED WITH A PEPTIDYL PYRIDINIUM METHYL KETONE CONTAINING BIVALENT INHIBITOR
Contents |
Overview
The crystal structure of a complex between a bivalent peptidyl pyridinium methyl ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp- Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal, active-site-directed portion of the inhibitor is linked to the fibrinogen recognition exosite binding portion by a tetraglycine segment. The strong electron-withdrawing effect provided by the permanent positive charge on the pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a covalent P596-thrombin complex is observed. The electron density surrounding the active site portion and the pyridinium of the inhibitor is very well defined, clearly showing the existence of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of the inhibitor. The decreased binding ability of thrombin inhibitors containing N-terminal acetylation is discussed as is the effect of replacing the P3 (D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the remainder of the inhibitor is generally well defined, the exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS)
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1HBT is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
Reference
Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin., Rehse PH, Steinmetzer T, Li Y, Konishi Y, Cygler M, Biochemistry. 1995 Sep 12;34(36):11537-44. PMID:7547884
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