Abstract
In this study the three-dimensional (3-D) model of the ligand-binding domain (V106-P322) of human interleukin-6 receptor (hIL-6 R) was constructed by computer-guided homology modeling technique using the crystal structure of the ligand-binding domain (K52-L251) of human growth hormone receptor (hGHR) as templet. Furthermore, the active binding region of the 3-D model of hIL-6R with the ligand (hIL-6) was predicted. In light of the structural characteristics of the active region, a hydrophobic pocket shielded by two hydrophilic residues (E115 and E505) of the region was identified by a combination of molecular modelling and the site-directed or double-site mutation of the twelve crucial residues in the ligand-binding domain of hIL-6R (V106-P322). We observed and analyzed the effects of these mutants on the spatial conformation of the pocket-like region of hIL-6 R. The results indicated that any site-directed mutation of the five Cys residues (four conservative Cys residues: Cys121, Cys132, Cys165, Cys176; near membrane Cys residue: Cys193) or each double-site mutation of the five residues in WSEWS motif of hIL-6R (V106-P322) makes the corresponding spatial conformation of the pocket region block the linkage between hIL-6 R and hIL-6. However, the influence of the site-directed mutation of Cys211 and Cys277 individually on the conformation of the pocket region benefits the interaction between hIL-6R and hIL-6. Our study suggests that the predicted hydrophobic pocket in the 3-D model of hIL-6R (V106-P322) is the critical molecular basis for the binding of hIL-6R with its ligand, and the active pocket may be used as a target for designing small hIL-6R-inhibiting molecules in our further study.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Li, S., Satoh, T., Korngold, R. et al., Proposed CD4 dimerization sites indicate a novel mode of co-oligomerization of CD4, MHC class II, and TCR molecules, Immunol. Today, 1998, 19(10): 455.
Li, S., Gao, J., Satoh, T. et al., A computer screening approach to immunoglobulin superfamily structures and interactions: Discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics, Proc. Nat. Acad. Sci. USA, 1997, 94(1): 73.
Satoh, T., Aramini, J.M., Li, S. et al., Bioactive peptide design based on protein surface epitopes: a cyclic heptapeptide mimics CD4 domain 1 CC′ loop and inhibits CD4 biological function, J. Biol. Chem., 1997, 272: 12175.
Simpson, R.J., Hammacher, A., Smith, D.K. et al., Interleukin-6: structure-function relationships, Protein Sci., 1997, 6(5): 929.
Papadaki, H., Kyriakou, D., Foudoulakis, A. et al., Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity, Acta Haematol., 1997, 97(4): 191.
Yamamura, M., Yamada, Y., Momita, S. et al., Circulating interleukin-6 levels are elevated in adult T-cell leukaemia/lymphoma patients and correlate with adverse clinical features and Survival, Br. J. Haematol., 1998, 100(1): 129.
Somers, W., Stahl, M., Seehra, J.S., 1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling, EMBO J., 1997, 16(5): 989.
Yawata, H., Yasukawa, K., Shunji, N. et al., Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues reguied for IL-6-binding and IL-6 signal transduction through gp130, EMBO J., 1993, 12: 1705.
Duan, J. B., Wang, J. X., Cai, X. et al., Characterization of a soluble IL-6 receptor a mutant C277D/H280I expressed inE. coli, Biochemistry and Molecular Biology International, 1997, 41(6): 1101.
Ren, Y. F., Qu, H., Feng, J. N. et al., Prediction of the active region in the extracellular ligand-binding domain of human interleukin-6 receptor, Chinese Science Bulletin, 2000, 45(3): 301.
Ren, Y. F., Guo, N., Zhang, H. Q. et al., Introduction and expression of the recombinant human IL-6 receptor gene in rat myelocytic leukaemia cells, Journal of Experimental Hematology (in Chinese), 1994, 2(1): 35.
Kruttgen, A., Rose-John, S., Dufhues, G. et al., The three carboxy-terminal amino acids of human interleukin-6 are essential for its biological activity, FEBS Lett., 1990, 273: 95.
Lutticken, C., Kruttgen, A., Moller, C. et al., Evidence for the importance of a positive charge and an α-helical structure of the C-terminus for biological activity of human IL-6, FEBS Lett., 1991, 282: 265.
Leebeek, F. W. G., Kariya, K., Sehwabe, M. et al., Identification of a receptor binding site in the carboxyl terminus of human interleukin-6, J. B. C., 1992, 267: 14832.
Stoddard, B. L., Koshland, D. E., Prediction of the structure of a receptor-protein complex using a binary docking method, Nature, 1992, 358: 774.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ren, Y., Feng, J., Qu, H. et al. Three-dimensional structure and function study on the active region in the extracellular ligand-binding domain of human IL-6 receptor. Sci. China Ser. C.-Life Sci. 43, 425–432 (2000). https://doi.org/10.1007/BF02879308
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02879308