Lackmann, Martin,Janes, Peter W.,Nikolov, Dimitar B.,Saha, Nayanendu
申请号：
AU2012201143
公开号：
AU2012201143A1
申请日:
2012.02.27
申请国别(地区):
AU
年份:
2012
代理人:
摘要：
#$%^&*AU2012201143A120120322.pdf#####ABSTRACT Elucidation of the crystal structure of an ADAM 10 substrate-recognition and proteinase-positioning module comprising the protein cysteine-rich and disintegrin domains, and detailed functional analysis revealed that an acidic pocket within the cysteine-rich domain forms a substrate-recognition site. The binding of this pocket to 5 receptor/ligand complexes facilitates effective ligand cleavage, which is prevented when critical residues within the pocket are changed. This provides use of the surface pocket within the extracellular domain of ADAM 10, and the corresponding structure in related proteases such as ADAM 17, as a target for structure-based computational and high-throughput screens for small-molecule substrate-specific inhibitors or 10 monoclonal antibodies that inhibit ADAM protease cleavage of ephrins and other ADAMIO or ADAM17 substrates. These inhibitors will be useful in therapeutic intervention of tumour development, invasion and metastasis and other diseases which involve the activity of the ADAM10 and ADAM17 proteases, such as inflammation, cardio-vascular disease, arthritis and other auto-immune diseases.
