Docking of human interleukin-15 to its specific receptor alpha chain: correlation between molecular modeling and mutagenesis experimental data.
A structural model of the sushi domain of IL-15Ralpha was first obtained by homology modeling to study its interactions with IL-15 by means of molecular modeling, peptide scanning, and site-directed mutagenesis. From these experimental data, a putative interacting surface of IL-15Ralpha with a previously published IL-15 model was inferred: Leu25, Leu44, and Glu46 of IL-15 and Arg35 of IL-15Ralpha were found to be key interfacial residues and were subsequently used as filters for the construction of docking solutions. Human IL-15/IL-15Ralpha complexes were constructed in two stages, with a preliminary docking procedure, treating the two partners as rigid bodies and using these filters. In this first stage, two classes of docking solutions were characterized. From a topological point of view, each solution could be derived from the other by reverse orientation of one partner in relation to the other. In a second stage, several further energy refinements clearly favored one solution. Moreover, this unique docking solution was confirmed by molecular modeling of IL-15 mutants previously built and tested in our laboratory. Finally, this complex model, which is a useful tool to study the IL-15/IL-15Ralpha interface, was topologically compared to IL-2/IL-2Ralpha complexes (previous model in the literature and recent crystal structure).
Quéméner
Agnès
A
INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes, France.
Bernard
Jérôme
J
Mortier
Erwan
E
Plet
Ariane
A
Jacques
Yannick
Y
Tran
Vinh
V
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D019409:Interleukin-15 / Q000737:chemistry* / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000737:chemistry* / Q000235:genetics; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment
D019409:Interleukin-15; D053645:Interleukin-2 Receptor alpha Subunit; D011994:Recombinant Proteins