2pgb: Difference between revisions

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[[Image:2pgb.jpg|left|200px]]
{{Seed}}
[[Image:2pgb.png|left|200px]]


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{{STRUCTURE_2pgb|  PDB=2pgb  |  SCENE=  }}  
{{STRUCTURE_2pgb|  PDB=2pgb  |  SCENE=  }}  


'''Inhibitor-free human thrombin mutant C191A-C220A'''
===Inhibitor-free human thrombin mutant C191A-C220A===




==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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{{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]
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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