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| Autor | Silva, Floriano P. | |
| Autor | Antunes, Octávio A. C. | |
| Autor | Alencastro, Ricardo B. de | |
| Autor | De Simone, Salvatore Giovanni | |
| Fecha de acceso | 2020-02-04T10:46:56Z | |
| Fecha de disponibilización | 2020-02-04T10:46:56Z | |
| Fecha de publicación | 2006 | |
| Referencia | SILVA JR., Floriano P. et al. The Na+ binding channel of human coagulation proteases: Novel insights on the structure and allosteric modulation revealed by molecular surface analysis. Biophysical Chemistry, v. 119, p. 282-294, 2006. | pt_BR |
| ISSN | 0301-4622 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/39689 | |
| Idioma | eng | pt_BR |
| Editor | Elsevier | pt_BR |
| Derechos de autor | restricted access | |
| Palabras clave en Portugués | Allostery | pt_BR |
| Palabras clave en Portugués | Ligação de Na + | pt_BR |
| Palabras clave en Portugués | Modelagem molecular | pt_BR |
| Palabras clave en Portugués | Trombina | pt_BR |
| Palabras clave en Portugués | Fatores de coagulação | pt_BR |
| Palabras clave en Portugués | Serina Proteases | pt_BR |
| Título | The Na+ binding channel of human coagulation proteases: novel insights on the structure and allosteric modulation revealed by molecular surface analysis | pt_BR |
| Tipo del documento | Article | |
| DOI | 10.1016/j.bpc.2005.10.001 | |
| Resumen en Inglés | Thrombovascular diseases result from imbalanced haemostasis and comprise important health problems in the aging population worldwide. The activity of enzymes pertaining to the coagulation cascade of mammalians exhibit several control mechanisms in order to maintain a proper balance between bleeding and thrombosis. For instance, human coagulation serine proteases carrying a F225 or Y225 are allosteric modulated by the binding of Na+ in a water-filled channel connected to the primary specificity pocket (S1 subsite) of these enzymes. We have characterized the structure, topography and lipophilicity of this channel in the ligand-free fast (sodium-bound) and slow (sodium-free) forms of thrombin, in the sole available structure of activated protein C and in several structures of the coagulation factors VIIa, IXa and Xa, differing in the nature of the bound inhibitor and in the occupancy of exosite-I as well as the Ca2+ and Na+ binding sites. Opposite to thrombin, the aqueous channels in all other coagulation enzymes sheltering a Na+ binding site do not have an aperture on the enzyme surface opposite to the S1 subsite entrance. In these enzymes, the lack of the three-residue insertion in loop 1 (183-189) as found in thrombin allied to compensatory mutations in the positions 187-185 and 222 effects a constriction in the water-filled channel that ends up by segregating the ion binding site from the S1 subsite. We also disclosed major topographical changes on the thrombin's surface upon sodium release and transition to the slow form that culminate in the narrowing of the S1 subsite entrance and, strikingly, in the loss of communication between the primary specificity pocket and the exosite-I. Such observation is in accordance with existing experimental data demonstrating thermodynamic linkage between these distant regions on the thrombin surface. Conformational changes in F34, L40, R73 and T74 were the main responsible for this effect. A path by which these changes in the vicinity of exosite-I could be transmitted to the S1 subsite and, consequently, to the sodium binding site is proposed. | pt_BR |
| Afiliación | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Bioquímica e Biologia Molecular. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Afiliación | Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Afiliación | Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Afiliación | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Bioquímica e Biologia Molecular. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ, Brasil / Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil. | pt_BR |
| Palavras clave en Inglês | Allostery | pt_BR |
| Palavras clave en Inglês | Na+ binding | pt_BR |
| Palavras clave en Inglês | Molecular modeling | pt_BR |
| Palavras clave en Inglês | Thrombin | pt_BR |
| Palavras clave en Inglês | Coagulation factors | pt_BR |
| Palavras clave en Inglês | Serine proteases | pt_BR |
| e-ISSN | 1873-4200 | |
| Fecha de embargo | 2025-01-01 |
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