Mechanism of GPCR activation based on endothelin abnormalities

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kurihara Yukiko 東京大学, 大学院医学系研究科(医学部), 講師 (80345040)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: GPCR / エンドセリン / 希少疾患

Outline of Final Research Achievements

Mutations of G-protein-coupled receptors (GPCRs) cause various human diseases. We present a patient with Mandibulofacial Dysostosis with Alopecia (MFDA) and mouse models carrying causative mutations in the gene encoding endothelin A receptor (ETAR), a class A GPCR. Additional mutagenesis and pharmacological experiments revealed the causative mutations as gain-of-function, dependent on the ligand endothelin3. To elucidate how amino acid substitutions far from the ligand binding site increase affinity, we use molecular dynamics simulation. The ETAR-E303K mutation, situated at the intracellular end of transmembrane helix 6, leads to G-protein-mediated enhancement of agonist affinity. The ETAR-Y129F mutation reduces the Na-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding.

Free Research Field

分子生物学、発生生物学

Academic Significance and Societal Importance of the Research Achievements

顎顔面骨形成不全症は希少疾患であるが、その原因遺伝子のエンドセリンA受容体はGPCRであるので、その変異による疾患発症メカニズムを明らかにすることは、生体で重要な役割を果たしているGPCR一般の活性化メカニズムを解明に大きく貢献することになる。これにより、薬剤の3-4割を占めるといわれているGPCRの創薬に貢献する。