TI  - Analysis of the human  <prot>interleukin-6</prot> /human  <prot><prot>interleukin-6</prot> receptor</prot> binding
      interface at the amino acid level: proposed mechanism of interaction.
PG  - 1319-33
AB  - The interaction between  <prot>interleukin-6</prot> (<prot>IL-6</prot>)  and  <prot><prot>IL-6</prot> receptor</prot> (<prot>IL-6R</prot>)  is
      the initial and most specific step in the <prot>IL-6</prot> signaling pathway.
      Understanding its mechanism at the amino acid level is the basis for
      developing small <prot>IL-6</prot>-inhibiting molecules. We studied the human  <prot>IL-6</prot>
      (<prot>hIL-6</prot>) / <prot>hIL-6R</prot>  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  <prot>hIL-6</prot>  and  <prot>hIL-6R</prot>  residues predicted to reside in the contact
      region and to interact with each other. We studied the capacity of these
      mutants to form an  <prot>IL-6</prot> / <prot>IL-6R</prot>  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.
AD  - Institut Pasteur de Bruxelles, Departement de Virologie, Belgium.
