Analysis of the human interleukin-6/human interleukin-6 receptor binding interface at the amino acid level: proposed mechanism of interaction.
The interaction between interleukin-6 (IL-6) and IL-6 receptor (IL-6R) is the initial and most specific step in the IL-6 signaling pathway. Understanding its mechanism at the amino acid level is the basis for developing small IL-6-inhibiting molecules. We studied the human IL-6 (hIL-6)/hIL-6R binding interface by a combination of molecular modelling and site-directed mutagenesis. Our model suggests that the center of the interface between the two molecules consists of hydrophobic contacts predicted to account for most of the binding-free energy. These contacts can be regarded as a hydrophobic core shielded by hydrophilic residues that are also needed for recognition. Following this hypothesis, we altered in hIL-6 and hIL-6R residues predicted to reside in the contact region and to interact with each other. We studied the capacity of these mutants to form an IL-6/IL-6R complex and their ability to transduce the signal. This combined approach has led to the identification of certain residue-clusters in the binding interface and to a rational explanation of their specific interactions, suggesting therein a likely mechanism of complex formation. The results confirm the predictive model and strongly support our hypothesis. Comparison with other cytokines and their alpha-subunit receptors suggests that the structural location of certain binding sites are conserved.
Kalai
M
M
Institut Pasteur de Bruxelles, Département de Virologie, Belgium.
Montero-Julian
F A
FA
Grötzinger
J
J
Fontaine
V
V
Vandenbussche
P
P
Deschuyteneer
R
R
Wollmer
A
A
Brailly
H
H
Content
J
J
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6