Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain.
The lymphocyte function-associated antigen (LFA-1) belongs to the family of beta2-integrins and plays an important role in T-cell activation and leukocyte migration to sites of inflammation. We report here that lovastatin, a drug clinically used for lowering cholesterol levels, inhibits the interaction of human LFA-1 with its counter-receptor intercellular adhesion molecule-1. Using nuclear magnetic resonance spectroscopy and X-ray crystallography we show that the inhibitor binds to a highly conserved domain of the LFA-1 alpha-chain called the I-domain. The first three-dimensional structure of an integrin inhibitor bound to its receptor reveals atomic details for a hitherto unknown mode of LFA-1 inhibition. It also sheds light into possible mechanisms of LFA-1 mediated signalling and will support the design of novel anti-adhesive and immunosuppressive drugs.
Kallen
J
J
Preclinical Research, NOVARTIS PHARMA AG, Basel, CH 4002, Switzerland.
Welzenbach
K
K
Ramage
P
P
Geyl
D
D
Kriwacki
R
R
Legge
G
G
Cottens
S
S
Weitz-Schmidt
G
G
Hommel
U
U
D000595:Amino Acid Sequence; D001665:Binding Sites; D018845:CD11 Antigens / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D014407:Tumor Cells, Cultured
D018845:CD11 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D008148:Lovastatin