Abstract
Recombinant human interferon alpha-2A (rhIFN-alpha-2A) has been crystallized in complex with the recombinantly produced Fab fragment of a therapeutic monoclonal antibody (MEDI545; IgG1/kappa) which targets several human interferon alpha subtypes. This constitutes the first reported crystals of a human type I interferon bound to an antibody. The orthorhombic crystals belonged to either space group I222 or I2(1)2(1)2(1), with unit-cell parameters a = 134.82, b = 153.26, c = 163.49 A. The diffraction of the crystals extended to 3.0 A resolution. The asymmetric unit contained two Fab-rhIFN-alpha-2A complexes. This corresponded to a crystal volume per protein weight (V(M)) of 3.02 A(3) Da(-1) and a solvent content of 59.3%. The corresponding three-dimensional structure is expected to shed light on the mechanism of action of MEDI545 and the molecular basis of its specificity.
Highlights
Type I interferons (IFNs) are a family of cytokines that are expressed from over 15 functional genes and include IFN, IFN, IFN, IFN, IFN-", IFN- and IFN-!
The IFN- family alone comprises at least 13 different subtypes (Foster & Finter, 1998) and is thought to play a role in systemic lupus erythematosus (SLE), type I diabetes, Sjogren’s syndrome and thyroid diseases (Selmi et al, 2006). This attractive targeting potential led to the development by MedImmune of MEDI545, a fully human monoclonal antibody which exhibits binding to multiple IFN- subtypes
Each chain was placed under the control of its own human cytomegalovirus major immediate early promoter and enhancer
Summary
Type I interferons (IFNs) are a family of cytokines that are expressed from over 15 functional genes and include IFN- , IFN- , IFN-, IFN-, IFN-", IFN- and IFN-!. The IFN- family alone comprises at least 13 different subtypes (Foster & Finter, 1998) and is thought to play a role in systemic lupus erythematosus (SLE), type I diabetes, Sjogren’s syndrome and thyroid diseases (Selmi et al, 2006). This attractive targeting potential led to the development by MedImmune of MEDI545, a fully human monoclonal antibody which exhibits binding to multiple IFN- subtypes. Three type I human interferon structures have previously been determined using either X-ray crystallography or NMR. The first reported diffracting crystals of a human type I interferon bound to an antibody are described and characterized
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