PMID- 7511100
OWN - NLM
STAT- MEDLINE
DCOM- 19940422
LR  - 20220511
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 13
IP  - 6
DP  - 1994 Mar 15
TI  - Generation of interleukin-6 receptor antagonists by molecular-modeling guided 
      mutagenesis of residues important for gp130 activation.
PG  - 1357-67
AB  - Interleukin-6 (IL-6) drives the sequential assembly of a receptor complex formed 
      by the IL-6 receptor (IL-6R alpha) and the signal transducing subunit, gp130. A 
      model of human IL-6 (hIL-6) was constructed by homology using the structure of 
      bovine granulocyte colony stimulating factor. The modeled cytokine was predicted 
      to interact sequentially with the cytokine binding domains of IL-6R alpha and 
      gp130 bridging them in a way similar to that of the interaction between growth 
      hormone and its homodimeric receptor. Several residues on helices A and C which 
      were predicted as contact points between IL-6 and gp130 and therefore essential 
      for IL-6 signal transduction, were subjected to site-directed mutagenesis 
      individually or in combined form. Interestingly, while single amino acid changes 
      never produced major alterations in IL-6 bioactivity, a subset of double mutants 
      of Y31 and G35 showed a considerable reduction of biological activity and were 
      selectively impaired from associating with gp130 in binding assays in vitro, 
      while they maintained wild-type affinity towards hIL-6-R alpha. More importantly, 
      we demonstrated the antagonistic effect of mutant Y31D/G35F versus wild-type 
      IL-6.
FAU - Savino, R
AU  - Savino R
AD  - Department of Genetics, Istituto di Ricerche di Biologia Molecolare P. Angeletti 
      (IRBM), Pomezia, Rome, Italy.
FAU - Lahm, A
AU  - Lahm A
FAU - Salvati, A L
AU  - Salvati AL
FAU - Ciapponi, L
AU  - Ciapponi L
FAU - Sporeno, E
AU  - Sporeno E
FAU - Altamura, S
AU  - Altamura S
FAU - Paonessa, G
AU  - Paonessa G
FAU - Toniatti, C
AU  - Toniatti C
FAU - Ciliberto, G
AU  - Ciliberto G
LA  - eng
PT  - Journal Article
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Antigens, CD)
RN  - 0 (IL6ST protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Interleukin)
RN  - 0 (Receptors, Interleukin-6)
RN  - 133483-10-0 (Cytokine Receptor gp130)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - 9002-72-6 (Growth Hormone)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - *Antigens, CD
MH  - CHO Cells
MH  - Cattle
MH  - Cricetinae
MH  - Crystallography, X-Ray
MH  - Cytokine Receptor gp130
MH  - Granulocyte Colony-Stimulating Factor/chemistry
MH  - Growth Hormone/chemistry
MH  - Humans
MH  - Interleukin-6/chemistry/genetics/metabolism
MH  - Membrane Glycoproteins/*metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Receptors, Interleukin/*antagonists & inhibitors/genetics/metabolism
MH  - Receptors, Interleukin-6
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
PMC - PMC394953
EDAT- 1994/03/15 00:00
MHDA- 1994/03/15 00:01
PMCR- 1995/03/15
CRDT- 1994/03/15 00:00
PHST- 1994/03/15 00:00 [pubmed]
PHST- 1994/03/15 00:01 [medline]
PHST- 1994/03/15 00:00 [entrez]
PHST- 1995/03/15 00:00 [pmc-release]
AID - 10.1002/j.1460-2075.1994.tb06389.x [doi]
PST - ppublish
SO  - EMBO J. 1994 Mar 15;13(6):1357-67. doi: 10.1002/j.1460-2075.1994.tb06389.x.