Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1beta.
Interleukin-1 (IL-1) is an important mediator of inflammatory disease. The IL-1 family currently consists of two agonists, IL-1alpha and IL-1beta, and one antagonist, IL-1ra. Each of these molecules binds to the type I IL-1 receptor (IL1R). The binding of IL-1alpha or IL-1beta to IL1R is an early step in IL-1 signal transduction and blocking this interaction may therefore be a useful target for the development of new drugs. Here we report the three-dimensional structure of IL-1beta bound to the extracellular domain of IL1R (s-IL1R) at 2.5 A resolution. IL-1beta binds to s-IL1R with a 1:1 stoichiometry. The crystal structure shows that s-IL1R consists of three immunoglobulin-like domains which wrap around IL-1beta in a manner distinct from the structures of previously described cytokine-receptor complexes. The two receptor-binding regions on IL-1beta identified by site-directed mutagenesis both contact the receptor: one binds to the first two domains of the receptor, while the other binds exclusively to the third domain.
Vigers
G P
GP
Amgen Inc., Boulder, Colorado 80301, USA.
Anderson
L J
LJ
Caffes
P
P
Brandhuber
B J
BJ
D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D017472:Receptors, Interleukin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins