2od3
From Proteopedia
(New page: 200px<br /> <applet load="2od3" size="450" color="white" frame="true" align="right" spinBox="true" caption="2od3, resolution 1.75Å" /> '''Human thrombin chim...) |
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| - | [[Image:2od3.gif|left|200px]]<br /> | + | [[Image:2od3.gif|left|200px]]<br /><applet load="2od3" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2od3" size=" | + | |
caption="2od3, resolution 1.75Å" /> | caption="2od3, resolution 1.75Å" /> | ||
'''Human thrombin chimera with human residues 184a, 186, 186a, 186b, 186c and 222 replaced by murine thrombin equivalents.'''<br /> | '''Human thrombin chimera with human residues 184a, 186, 186a, 186b, 186c and 222 replaced by murine thrombin equivalents.'''<br /> | ||
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==Overview== | ==Overview== | ||
Unlike human thrombin, murine thrombin lacks Na(+) activation due to the, charge reversal substitution D222K in the Na(+) binding loop. However, the, enzyme is functionally stabilized in a Na(+)-bound form and is highly, active toward physiologic substrates. The structural basis of this, peculiar property is unknown. Here, we present the 2.2 A resolution x-ray, crystal structure of murine thrombin in the absence of inhibitors and, salts. The enzyme assumes an active conformation, with Ser-195, Glu-192, and Asp-189 oriented as in the Na(+)-bound fast form of human thrombin., Lys-222 completely occludes the pore of entry to the Na(+) binding site, and positions its side chain inside the pore, with the Nzeta atom H-bonded, to the backbone oxygen atoms of Lys-185, Asp-186b, and Lys-186d. The same, architecture is observed in the 1.75 A resolution structure of a thrombin, chimera in which the human enzyme carries all residues defining the Na(+), pore in the murine enzyme. These findings demonstrate that Na(+), activation in thrombin is linked to the architecture of the Na(+) pore., The molecular strategy of Na(+) activation mimicry unraveled for murine, thrombin is relevant to serine proteases and enzymes activated by, monovalent cations in general. | Unlike human thrombin, murine thrombin lacks Na(+) activation due to the, charge reversal substitution D222K in the Na(+) binding loop. However, the, enzyme is functionally stabilized in a Na(+)-bound form and is highly, active toward physiologic substrates. The structural basis of this, peculiar property is unknown. Here, we present the 2.2 A resolution x-ray, crystal structure of murine thrombin in the absence of inhibitors and, salts. The enzyme assumes an active conformation, with Ser-195, Glu-192, and Asp-189 oriented as in the Na(+)-bound fast form of human thrombin., Lys-222 completely occludes the pore of entry to the Na(+) binding site, and positions its side chain inside the pore, with the Nzeta atom H-bonded, to the backbone oxygen atoms of Lys-185, Asp-186b, and Lys-186d. The same, architecture is observed in the 1.75 A resolution structure of a thrombin, chimera in which the human enzyme carries all residues defining the Na(+), pore in the murine enzyme. These findings demonstrate that Na(+), activation in thrombin is linked to the architecture of the Na(+) pore., The molecular strategy of Na(+) activation mimicry unraveled for murine, thrombin is relevant to serine proteases and enzymes activated by, monovalent cations in general. | ||
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| - | ==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== | ||
| - | 2OD3 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 NAG as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2OD3 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=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OD3 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:53:23 2008'' |
Revision as of 12:53, 23 January 2008
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Human thrombin chimera with human residues 184a, 186, 186a, 186b, 186c and 222 replaced by murine thrombin equivalents.
Overview
Unlike human thrombin, murine thrombin lacks Na(+) activation due to the, charge reversal substitution D222K in the Na(+) binding loop. However, the, enzyme is functionally stabilized in a Na(+)-bound form and is highly, active toward physiologic substrates. The structural basis of this, peculiar property is unknown. Here, we present the 2.2 A resolution x-ray, crystal structure of murine thrombin in the absence of inhibitors and, salts. The enzyme assumes an active conformation, with Ser-195, Glu-192, and Asp-189 oriented as in the Na(+)-bound fast form of human thrombin., Lys-222 completely occludes the pore of entry to the Na(+) binding site, and positions its side chain inside the pore, with the Nzeta atom H-bonded, to the backbone oxygen atoms of Lys-185, Asp-186b, and Lys-186d. The same, architecture is observed in the 1.75 A resolution structure of a thrombin, chimera in which the human enzyme carries all residues defining the Na(+), pore in the murine enzyme. These findings demonstrate that Na(+), activation in thrombin is linked to the architecture of the Na(+) pore., The molecular strategy of Na(+) activation mimicry unraveled for murine, thrombin is relevant to serine proteases and enzymes activated by, monovalent cations in general.
About this Structure
2OD3 is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Structural basis of na+ activation mimicry in murine thrombin., Marino F, Chen ZW, Ergenekan CE, Bush-Pelc LA, Mathews FS, Di Cera E, J Biol Chem. 2007 Jun 1;282(22):16355-61. Epub 2007 Apr 10. PMID:17428793
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