Three-Dimensional Structure of Interleukin-2

Abstract

Interleukin-2 is an effector protein that participates in modulating the immune response; it has become a focal point for the study of lymphokine structure and function. The three-dimensional structure of the interleukin molecule has been solved to 3.0 angstrom resolution. Interleukin-2 has a novel alpha-helical tertiary structure that suggests one portion of the molecule forms a structural scaffold, which underlies the receptor binding facets of the molecule.

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…3) determined in 1987 (Brandhuber et al 1987). IL-2 is a compact globular protein, composed of four tightly packed a-helices adopting a down-down-up-up configuration (cytokine fold) common to many interleukins and (Bazan 1990;Rozwarski et al 1994).…”

Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

“…The integrity of this disulfide is required for biological activity (Ju et al, 1987). A free Cys 125, present in IL-2 and conserved throughout species (Bazan, 1992), does not have counterparts in GM-CSF or IL-4 and is not important to the function, because the alanine mutant used in crystal structure solution has identical activity (Brandhuber et al, 1987). None of these disulfides corresponds directly to the ones in 1L-4, although Cys 121 in GM-CSF is a structural equivalent of Cys 127 in IL-4.…”

“…The latter residue is buried in the hydrophobic core, so the significance of this observation is unclear. Zurawski and Zurawski (1988) identified helix B of IL-2 as important to activity, while the region identified as helix B by SauvC et al (1991) was in reality the loop AB, and the misidentification was the result of the use of the obsolete model of Brandhuber et al (1987).…”

“…and GM-CSF, as well as direct sequence alignment of IL-2 with the other two cytokines, that the originally published crystal structure of IL-2 (Brandhuber et al, 1987) could not be correct. Similar conclusions were also reached on the basis of structural studies of IL-2 utilizing the technique of multidimensional NMR (Mott et al, 1992).…”

“…Medium-to high-resolution structures of several of the hematopoietins have now been determined by X-ray crystallography and NMR. These include GM-CSF (Diederichs et al, 1991;Walter et al, 1992a), macrophage colony-stimulating factor (Pandit et al, 1992), granulocyte colony-stimulating factor (Hill et al, 1993), IL-5 (Milburn et al, 1993), the recently corrected structure of IL-2 (Brandhuber et al, 1987;McKay, 1992), and the crystal and NMR structures of IL-4, determined independently in four different laboratories (Powers et al, 1992;Smith et al, 1992; 1992b; Wlodawer et al, 1992). Structures of other molecules with similar folds, for example, porcine (AbdelMeguid et al, 1987) and human (de Vos et al, 1992) growth hormones, were also determined crystallographically.…”