Structural and Inhibition Analysis Reveals the Mechanism of Selectivity of a Series of Aggrecanase Inhibitors
By M. Tortorella, A. Tomasselli, K. Mathis, M. Schnute, S. S. Woodard, G. Munie, Jennifer M. Williams, N. Caspers, A. Wittwer, A. Malfait and 1 more. 2009
54 citations recorded by the source corpus.
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.
Subfields: Biotechnology, Molecular Biology, Oncology
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
In Oncology
Citations in the corpus
- The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “These compounds are potent inhibitors of ADAMTS4 and 5, with Ki values in the low nM range and selectivity two orders of magnitude greater than that of the MMPs, suggesting that they are good platforms for the development of highly selective aggrecanase inhibitors [40].”