Structural and Inhibition Analysis Reveals the Mechanism of Selectivity of a Series of Aggrecanase Inhibitors
AUTOR(ES)
Tortorella, Micky D.
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2782012Documentos Relacionados
- Structure of Aquaporin Reveals Mechanism for Transport Selectivity
- Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors
- Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors.
- Measuring and interpreting the selectivity of protein kinase inhibitors
- Evolving potassium channels by means of yeast selection reveals structural elements important for selectivity
