2023 Fiscal Year Final Research Report
Structural biology of GC-A receptor - Mechanism underlying peptide recognition and intramolecular signal transduction
| Project/Area Number |
21K06044
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 43020:Structural biochemistry-related
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| Research Institution | University of Shizuoka (2023)
Juntendo University (2021-2022) |
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Principal Investigator |
Kodama Masami 静岡県立大学, 薬学部, 助教 (30512248)
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| Co-Investigator(Kenkyū-buntansha) |
小川 治夫 京都大学, 薬学研究科, 准教授 (40292726)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | GC受容体 / ナトリウム利尿ペプチド |
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| Outline of Final Research Achievements |
This study investigated the mechanism underlying guanylyl cyclase-A (GC-A)-dependent peptide recognition through the determination of the crystal structures of the GC-A extracellular ligand-binding (LB) domain complexed with full-length atrial natriuretic peptide (ANP), truncated mutants of ANP, and dendroaspis natriuretic peptide (DNP). The bound peptides possessed pseudo-two-fold symmetry, despite the lack of two-fold symmetry in the primary sequences, which enabled the tight coupling of the peptide to the receptor, and evidently contributes to guanylyl cyclase activity. The binding of DNP to the GC-A was essentially identical to that of ANP; however, the affinity of DNP for GC-A was higher than that of ANP owing to the additional interactions between distinctive sequences in the DNP and GC-A. Consequently, our findings provide valuable insights that can be applied to the development of novel agonists for the treatment of various human diseases.
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| Free Research Field |
細胞分子生物学、生化学
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| Academic Significance and Societal Importance of the Research Achievements |
GCase・ANP系は血圧・体液バランスの維持に不可欠で、急性心不全治療薬として広く臨床で利用されているにも関わらず、構造学的基盤の解析が遅れてきた。これは点対称の二量体GCaseの中心にANPが疑似対称性を獲得して結合するという構造が、構造決定を阻んできたためだが、この難問を我々は独自の技術を用いて克服した。GCase受容体の活性化はLBドメインの旋回に因るが、このような様式で活性化する受容体は他に報告例がなく、学術的に意義深い。ANPには血中半減期が短いという致命的な問題があり、DNPをはじめ、これに代わる医薬品の開発は急務である。本研究で得た知見は、医学的重要性も極めて高い。
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