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Volume 272, Number 36, Issue of September 5, 1997 pp. 22630-22641
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Receptor Binding Site of Human Interleukin-3 Defined by Mutagenesis and Molecular Modeling

(Received for publication, April 10, 1997, and in revised form, June 13, 1997)

From G. D. Searle and Company, St. Louis, Missouri 63198

Interleukin-3 (IL-3) is a member of the cytokine superfamily that promotes multi-potential hematopoietic cell growth by interacting with a cell surface receptor composed of  and  chains. The newly available three-dimensional structure of a variant of human (h) IL-3 allowed us to evaluate new and existing mutagenesis data and to rationally interpret the structure-function relationship of hIL-3 on a structural basis. The amino acid residues that were identified to be important for hIL-3 activity are grouped into two classes. The first class consists of largely hydrophobic residues required for the structural integrity of the protein, including the residues in IL-3 that are largely conserved among 10 mammalian species. These residues form the core of a scaffold for the second class of more rapidly diverging solvent-exposed residues, likely to be required for interaction with the receptor. Ten important and solvent-exposed residues, Asp²¹, Gly⁴², Glu⁴³, Gln⁴⁵, Asp⁴⁶, Met⁴⁹, Arg⁹⁴, Pro⁹⁶, Phe¹¹³, and Lys¹¹⁶, map to one side of the protein and form a putative binding site for the  subunit of the receptor. A model of the IL-3·IL-3 receptor complex based on the human growth hormone (hGH)·hGH soluble receptor complex structure suggests that the interface between IL-3 and the IL-3 receptor  subunit consists of a cluster of hydrophobic residues flanked by electrostatic interactions. Although the IL-3/IL-3 receptor  subunit interface cannot be uniquely located due to the lack of sufficient experimental data, several residues of the  subunit that may interact with Glu²² of IL-3 are proposed. The role of these residues can be tested in future mutagenesis studies to define the interaction between IL-3 and IL-3 receptor  subunit.

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