Alexander Zdanov Abstract

Interleukin-10 (IL-10) is a cytokine the primary function of which appears to be to limit and control inflammatory responses. It signals through interactions with two receptor chains: high affinity IL-10R1 and low affinity IL-10R2. Initially IL-10 interacts with IL-10R1, forming an intermediate complex with a binding site for the second receptor chain. Subsequent binding of the IL-10R2 completes the final complex. Human IL-10 is an intercalated dimer of two subunits, each consisting of 160 amino acid residues. Almost 85% of the residues of each subunit are involved in the formation of six a-helices, designated A-F. Helices E and F of each subunit mutually exchange with the helices E' and F' of another subunit, forming two compact six a-helix bundle domains of IL-10. The structure of the intermediate complex of IL-10 with an extracellular domain of IL-10R1 (sIL-10R1) consists of one molecule of IL-10 and two copies of the receptor bound to each domain of the IL-10 dimer. The molecule is positioned on the two-fold symmetry axis so that both domains of IL-10 and the sIL-10R1 moieties are exact copies of each other. The structures of both the free and receptor-bound IL-10 molecules are essentially the same. The structure of the sIL-10R1 molecule consists of two-domains, each having fibronection type III-like topology. Most of the interactions in the ligand/receptor interface are of polar nature, yet with two hydrophobic patches around the side chains ofTyr43 and Phe143 of the receptor. The position and structure of the binding site for the second receptor chain, IL-10R2, is still unclear.

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