2pgb

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{{STRUCTURE_2pgb| PDB=2pgb | SCENE= }}
{{STRUCTURE_2pgb| PDB=2pgb | SCENE= }}
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'''Inhibitor-free human thrombin mutant C191A-C220A'''
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===Inhibitor-free human thrombin mutant C191A-C220A===
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==Overview==
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Little is known on the role of disulfide bonds in the catalytic domain of serine proteases. The Cys-191-Cys-220 disulfide bond is located between the 190 strand leading to the oxyanion hole and the 220-loop that contributes to the architecture of the primary specificity pocket and the Na+ binding site in allosteric proteases. Removal of this bond in thrombin produces an approximately 100-fold loss of activity toward several chromogenic and natural substrates carrying Arg or Lys at P1. Na+ activation is compromised, and no fluorescence change can be detected in response to Na+ binding. A 1.54-A resolution structure of the C191A/C220A mutant in the free form reveals a conformation similar to the Na+-free slow form of wild type. The lack of disulfide bond exposes the side chain of Asp-189 to solvent, flips the backbone O atom of Gly-219, and generates disorder in portions of the 186 and 220 loops defining the Na+ site. This conformation, featuring perturbation of the Na+ site but with the active site accessible to substrate, offers a possible representation of the recently identified E* form of thrombin. Disorder in the 186 and 220 loops and the flip of Gly-219 are corrected by the active site inhibitor H-D-Phe-Pro-Arg-CH(2)Cl, as revealed by the 1.8-A resolution structure of the complex. We conclude that the Cys-191-Cys-220 disulfide bond confers stability to the primary specificity pocket by shielding Asp-189 from the solvent and orients the backbone O atom of Gly-219 for optimal substrate binding. In addition, the disulfide bond stabilizes the 186 and 220 loops that are critical for Na+ binding and activation.
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The line below this paragraph, {{ABSTRACT_PUBMED_17636263}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 17636263 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17636263}}
==Disease==
==Disease==
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==Reference==
==Reference==
Important role of the cys-191 cys-220 disulfide bond in thrombin function and allostery., Bush-Pelc LA, Marino F, Chen Z, Pineda AO, Mathews FS, Di Cera E, J Biol Chem. 2007 Sep 14;282(37):27165-70. Epub 2007 Jul 18. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17636263 17636263]
Important role of the cys-191 cys-220 disulfide bond in thrombin function and allostery., Bush-Pelc LA, Marino F, Chen Z, Pineda AO, Mathews FS, Di Cera E, J Biol Chem. 2007 Sep 14;282(37):27165-70. Epub 2007 Jul 18. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17636263 17636263]
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Molecular dissection of Na+ binding to thrombin., Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E, J Biol Chem. 2004 Jul 23;279(30):31842-53. Epub 2004 May 19. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15152000 15152000]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Serine protease]]
[[Category: Serine protease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:30:20 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:57:09 2008''

Revision as of 18:57, 28 July 2008

Image:2pgb.png

Template:STRUCTURE 2pgb

Contents

Inhibitor-free human thrombin mutant C191A-C220A

Template:ABSTRACT PUBMED 17636263

Disease

Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

2PGB is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Important role of the cys-191 cys-220 disulfide bond in thrombin function and allostery., Bush-Pelc LA, Marino F, Chen Z, Pineda AO, Mathews FS, Di Cera E, J Biol Chem. 2007 Sep 14;282(37):27165-70. Epub 2007 Jul 18. PMID:17636263

Molecular dissection of Na+ binding to thrombin., Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E, J Biol Chem. 2004 Jul 23;279(30):31842-53. Epub 2004 May 19. PMID:15152000

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