Small molecule designed to target metal binding site in the alpha2I domain inhibits integrin function

Integrin alpha2beta1 is a potential target molecule in drug development. We have established "design" criteria for molecules that bind to the "closed" conformation of alpha2I domain via Mg(2+) in MIDAS (metal ion dependent adhesion site) while simultaneously forming interactions...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-05, Vol.50 (11), p.2742-2746
Main Authors: Käpylä, Jarmo, Pentikäinen, Olli T, Nyrönen, Tommi, Nissinen, Liisa, Lassander, Sanna, Jokinen, Johanna, Lahti, Matti, Marjamäki, Anne, Johnson, Mark S, Heino, Jyrki
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Cations, Divalent
Cell Adhesion
CHO Cells
Cricetinae
Cricetulus
Drug Design
Humans
Integrins - antagonists & inhibitors
Integrins - chemistry
Integrins - metabolism
Magnesium - metabolism
Models, Molecular
Protein Conformation
Protein Structure, Tertiary
Streptomyces - chemistry
Tetracyclines - chemistry
Tetracyclines - isolation & purification
Tetracyclines - pharmacology
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Summary:Integrin alpha2beta1 is a potential target molecule in drug development. We have established "design" criteria for molecules that bind to the "closed" conformation of alpha2I domain via Mg(2+) in MIDAS (metal ion dependent adhesion site) while simultaneously forming interactions with neighboring amino acid residues. Specific tetracyclic Streptomyces products belonging to the group of aromatic polyketides fulfill our criteria and inhibit alpha2beta1 integrin. All previously described inhibitors of alphaI domain integrins act in an allosteric manner.
ISSN:0022-2623