PMID- 9028955
OWN - NLM
STAT- MEDLINE
DCOM- 19970317
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 89
IP  - 4
DP  - 1997 Feb 15
TI  - Analysis of the human interleukin-6/human interleukin-6 receptor binding 
      interface at the amino acid level: proposed mechanism of interaction.
PG  - 1319-33
AB  - 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.
FAU - Kalai, M
AU  - Kalai M
AD  - Institut Pasteur de Bruxelles, Departement de Virologie, Belgium.
FAU - Montero-Julian, F A
AU  - Montero-Julian FA
FAU - Grotzinger, J
AU  - Grotzinger J
FAU - Fontaine, V
AU  - Fontaine V
FAU - Vandenbussche, P
AU  - Vandenbussche P
FAU - Deschuyteneer, R
AU  - Deschuyteneer R
FAU - Wollmer, A
AU  - Wollmer A
FAU - Brailly, H
AU  - Brailly H
FAU - Content, J
AU  - Content J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antigens, CD)
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Interleukin)
RN  - 0 (Receptors, Interleukin-6)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antibodies, Monoclonal/immunology
MH  - Antigens, CD/*chemistry/genetics/metabolism
MH  - Binding Sites
MH  - Chemical Phenomena
MH  - Chemistry, Physical
MH  - Humans
MH  - Interleukin-6/*chemistry/genetics/metabolism
MH  - Melanoma/pathology
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Protein Binding
MH  - *Protein Conformation
MH  - Receptors, Cell Surface/chemistry
MH  - Receptors, Interleukin/*chemistry/genetics/metabolism
MH  - Receptors, Interleukin-6
MH  - Sequence Alignment
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
EDAT- 1997/02/15 00:00
MHDA- 1997/02/15 00:01
CRDT- 1997/02/15 00:00
PHST- 1997/02/15 00:00 [pubmed]
PHST- 1997/02/15 00:01 [medline]
PHST- 1997/02/15 00:00 [entrez]
AID - S0006-4971(20)58856-3 [pii]
PST - ppublish
SO  - Blood. 1997 Feb 15;89(4):1319-33.