Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors
| Autor: | Grace E. Munie, Nicole Caspers, Alfredo G. Tomasselli, Karl J. Mathis, Jennifer M. Williams, Mark E. Schnute, Anne-Marie Malfait, Arthur J. Wittwer, Micky D. Tortorella, Scott S. Woodard, Huey-Sheng Shieh |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Crystal structure Biochemistry Protein structure Hydrolase Endopeptidases Animals Humans Chelation Metalloprotease inhibitor Enzyme Inhibitors Molecular Biology Aggrecanase Hydrogen bond Chemistry Hydrogen Bonding Cell Biology Protein Structure Tertiary ADAM Proteins Zinc Structural Homology Protein Protein Structure and Folding ADAMTS4 Protein Cattle ADAMTS5 Protein Selectivity Procollagen N-Endopeptidase |
| Zdroj: | The Journal of biological chemistry. 284(36) |
| ISSN: | 0021-9258 |
| Popis: | Several inhibitors of a series of cis-1(S)2(R)-amino-2-indanol-based compounds were reported to be selective for the aggrecanases, ADAMTS-4 and -5 over other metalloproteases. To understand the nature of this selectivity for aggrecanases, the inhibitors, along with the broad spectrum metalloprotease inhibitor marimastat, were independently bound to the catalytic domain of ADAMTS-5, and the corresponding crystal structures were determined. By comparing the structures, it was determined that the specificity of the relative inhibitors for ADAMTS-5 was not driven by a specific interaction, such as zinc chelation, hydrogen bonding, or charge interactions, but rather by subtle and indirect factors, such as water bridging, ring rigidity, pocket size, and shape, as well as protein conformation flexibility. |
| Databáze: | OpenAIRE |
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