A model of the ternary complex of interleukin-10 with its soluble receptors.
BACKGROUND
Interleukin-10 (IL-10) is a cytokine whose main biological function is to suppress the immune response by induction of a signal(s) leading to inhibition of synthesis of a number of cytokines and their cellular receptors. Signal transduction is initiated upon formation of a ternary complex of IL-10 with two of its receptor chains, IL-10R1 and IL-10R2, expressed on the cell membrane. The affinity of IL-10R1 toward IL-10 is very high, which allowed determination of the crystal structure of IL-10 complexed with the extracellular/soluble domain of IL-10R1, while the affinity of IL-10R2 toward either IL-10 or IL-10/sIL-10R1 complex is quite low. This so far has prevented any attempts to obtain structural information about the ternary complex of IL-10 with its receptor chains.


RESULTS
Structures of the second soluble receptor chain of interleukin-10 (sIL-10R2) and the ternary complex of IL-10/sIL-10R1/sIL-10R2 have been generated by homology modeling, which allowed us to identify residues involved in ligand-receptor and receptor-receptor interactions.


CONCLUSIONS
The previously experimentally determined structure of the intermediate/binary complex IL-10/sIL-10R1 is the same in the ternary complex. There are two binding sites for the second receptor chain on the surface of the IL-10/sIL-10R1 complex, involving both IL-10 and sIL-10R1. Most of the interactions are hydrophilic in nature, although each interface includes two internal hydrophobic clusters. The distance between C-termini of the receptor chains is 25 A, which is common for known structures of ternary complexes of other cytokines. The structure is likely to represent the biologically active signaling complex of IL-10 with its receptor on the surface of the cell membrane.
Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA. svp@ncifcrf.gov
Sergei
S
Pletnev
Eugenia
E
Magracheva
Alexander
A
Wlodawer
Alexander
A
Zdanov
D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D017353:Gene Deletion; D006031:Glycosylation; D006801:Humans; D006860:Hydrogen Bonding; D016753:Interleukin-10 / Q000737:chemistry*; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017471:Receptors, Interferon / Q000737:chemistry; D018123:Receptors, Interleukin / Q000737:chemistry*; D053701:Receptors, Interleukin-10; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D008024:Ligands; D010455:Peptides; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10