MOLECULAR-MODELS OF 2 COMPETITIVE INHIBITORS, IL-2-DELTA-2 AND IL-2-DELTA-3, GENERATED BY ALTERNATIVE SPLICING OF HUMAN INTERLEUKIN-2

Molecular models of IL-2 delta 2 and IL-2 delta 3, two alternative spl ice variants of human IL-2 without exon 2 and 3, respectively, are des cribed. These alternative splice variants attract particular interest as potential competitive inhibitors of the cytokine. Tertiary structur e of IL-2 consists of four-helix bundle including helices A, B, C and D and a beta-pleated sheet. Exon 2 encodes the A-B loop (Asn30-Lys49 r esidues) linking helices A and B running in one direction. Rotation of the helix A around putative centre during the construction of IL-2 de lta 2 model have not produced any significant changes in the hydrophob ic core of IL-2 molecule. However, a large hole was formed on the surf ace of IL-2 delta 2 molecule instead of A-B loop in IL-2 fold. A high affinity IL-2 receptor is formed by combination of alpha, beta, and ga mma(c) chains. Comparison of the model of the receptor bound IL-2 with the model of IL-2 delta 2 has shown that their beta-chain binding sit es have minimum differences as distinct from alpha and gamma(c) chain- binding sites. Exon 3 encodes Ala50-Lys97 fragment which forms helices B and C with their short connecting loop. Model IL-2 delta 3 consists of helices A and D and long linking loop. This loop was composed of A -B and C-D loops which run in opposite directions in IL-2 structure an d contain beta-strands making a beta-pleated sheet. Conformation of th e linking loop relatively to helices A and D was stabilized by creatio n of a disulphide bond between cysteines 105 and 125. In addition, the hydrophobic residues of beta-sheet interact with the hydrophobic surf ace of A-D helical complex and close the latter from contacts with sol ution. Comparison of the model of IL-2 bound to receptor with IL-2 del ta 3 model has shown that absence of helices B and C in IL-2 delta 3 m odel results in insignificant conformational changes only in residues interacting with gamma(c) chain of the receptor. The beta/gamma(c) het erodimer is an intermediate affinity receptor of IL-2. Most likely, bo th IL-2 delta 2 and IL-2 delta 3 are naturally occurring IL-2 antagoni sts since they keep the ability of binding with an intermediate affini ty receptor of this cytokine and fail to engage the alpha chain of its high affinity receptor. (C) 1998 Elsevier Science B.V. All rights res erved.