High-Resolution Crystal Structure of the Snake Venom Metalloproteinase BaP1 Complexed with a Peptidomimetic: Insight into Inhibitor Binding
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| Autores: | , , , |
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| Formato: | artículo original |
| Fecha de Publicación: | 2009 |
| Descripción: | BaP1, a zinc-dependent endopeptidase belonging to the P-I class of snake venom metalloproteinases, exerts multiple tissue-damaging activities, leading to hemorrhage, myonecrosis, dermonecrosis, blistering, and edema. Interestingly, this metalloproteinase shows a high degree of structural homology with the catalytic domain of human adamalysins and matrix metalloproteinases, especially at the strictly conserved zinc binding motif and the so-called Met turn. This highlights BaP1 as an interesting model concerning inhibitor design for several medicinally important metalloproteinases, such as tumor necrosis factor alpha converting enzyme. Here, we report the first crystal structure of BaP1 complexed with a peptidomimetic inhibitor. Suitable crystals were obtained at four different pH values (4.6, 6.5, 7.5, and 8.0), and four high-resolution structures (1.46, 1.14, 1.08, and 1.05 A) were established. These structures and the detailed analysis of the structure-activity relationship of the bound inhibitor form a basis for the design of potent BaP1 inhibitors. The latter can be used for the treatment of local pathological effects caused by snake bites, mainly due to metalloproteinases such as BaP1. Besides, the high-resolution structure is an excellent starting point for the rational development of inhibitors for human metalloproteinases. The finding of a flexible loop region may have a great impact on further studies as to date little is known about the structural dependencies of the hemorrhagic activity of snake venom metalloproteinases. |
| País: | Kérwá |
| Institución: | Universidad de Costa Rica |
| Repositorio: | Kérwá |
| OAI Identifier: | oai:kerwa.ucr.ac.cr:10669/29255 |
| Acceso en línea: | http://pubs.acs.org/doi/abs/10.1021/bi9002315 https://hdl.handle.net/10669/29255 |
| Palabra clave: | Animals Biocatalysis Bothrops Catalytic Domain Crystallography, X-Ray Hydrogen-Ion Concentration Kinetics Metalloendopeptidases Models, Molecular Molecular Structure Protease Inhibitors Protein Binding Protein Conformation Viper Venoms Water Zinc Snake venom |