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 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.
Käpylä
Jarmo
J
Department of Biochemistry and Food Chemistry, University of Turku, FI-20014 Turku, Finland.
Pentikäinen
Olli T
OT
Nyrönen
Tommi
T
Nissinen
Liisa
L
Lassander
Sanna
S
Jokinen
Johanna
J
Lahti
Matti
M
Marjamäki
Anne
A
Johnson
Mark S
MS
Heino
Jyrki
J
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002413:Cations, Divalent; D002448:Cell Adhesion; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013302:Streptomyces / Q000737:chemistry; D013754:Tetracyclines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
D002413:Cations, Divalent; D016023:Integrins; D013754:Tetracyclines; D008274:Magnesium