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NMR studies of human interleukin-6 and its mutants

Research Project

Project/Area Number 07672310
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

NISHIMURA Chiaki  Univ. of Tokyo, Fac. of Pharmoceutical Sciences, Research Associate, 薬学部, 助手 (70218197)

Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1996: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsIL-6 / NMR / DSC / CD / Mutants / Structure-function relationship / Structive-stability relationship
Research Abstract

On the basis of the partial signal assignments and the observed NOE network, the folding topology of human IL-6 was analyzed. A comparison of the folding topology of IL-6 with that of human G-CSF indicated that IL-6 has a significant similarity of folding topology to that of G-CSF.DSC thermogram of the wild-type IL-6 at pH 4.2 showed two endothermic peaks at 35 and 65゚C,indicating that an intermediate state exists in the heat-denaturation pathway. In order to understand the structure-function and structure-stability relationships in the human IL-6 system, comparative studies were performed on the basis of NMR,DSC,and CD data obtained using the wild-type IL-6 and six mutants (L152V,L159V,L166V,L168V,L175V,and L182V). The NMR data showed that L182V substitution induced no structural change in IL-6, suggesting that Leu182 is located on the surface of the IL-6 molecule. A significant decrease in receptor-binding activity was observed in the L182V mutant. It was concluded that the side-chai … More n of Leu182 is directly involved in receptor-binding. L175V substitution was shown to induce a significant structural change in IL-6. It is possible that helix D bent more sharply toward helix B in the L175V mutant than in the wild-type IL-6 to maintain a closely packed and solvent-inaccessible core formed in the mutated region. It is suggested that the kink of helix D is related to the decrease in receptor-binding activity in the L175V mutant. In the case of L152V mutant, a significant structural changes were observed compared with the wild-type IL-6. However, no difference in receptor-binding activity between the wild-type IL-6 and L152V mutant was observed. The DSC data revealed that the partial unfolding of L152V mutant and the full unfolding of L175V mutant occurred at temperatures lower than those of the wild-type IL-6. The NMR data observed at various temperatures showed that L152V and L175V mutants are prone to the soluble self-association and insoluble precipitation, respectively, compared with the wild-type IL-6. Less

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (5 results)

All Other

All Publications (5 results)

  • [Publications] Nishimura,C.: "Folding Topologies of Human Interleukin-6 and Its Mutants As Studied by NMR Spectroscopy" Biochemistry. 35. 273-281 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 西村千秋: "IL-6の高次構造" 臨床免疫. 27. 990-996 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] I.C.Nishimura, A.Watanabe, H.Gouda, I.Shimada, and Y.Arata: "Folding Topologies of Human Interleukin-6 and Its Mutants As Studied by NMR Spectroscopy" Biochemistry. 35. 273-281 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Chiaki・Nishimura: "Folding Topologies of Human Interleukin-6 and Its Mutants As Studied by NMR Spectroscopy" Biochemistry. 35. 273-281 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 西村千秋: "IL-6の高次構造" 臨床免疫. 27. 990-996 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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