Structural Study of Human Dopamine D2 Receptor

• Project/Area Number: 15K18376
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kyoto University
• Principal Investigator: Im Dohyun 京都大学, 医学研究科, 特定研究員 (50721883)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Gタンパク質共役受容体 / GPCR / X線結晶構造解析 / 膜タンパク質 / 膜蛋白質 / 神経伝達物質・受容体 / 結晶構造解析

Outline of Final Research Achievements

The neurotransmitter dopamine controls numerous physiological functions in the brain and periphery via dopamine receptors in the G-protein-coupled receptor superfamily. Five dopamine receptors (DRD1-DRD5) are found in humans and DRD2 plays important pharmacological roles in numerous human disorders related to dopaminergic dysfunction, such as schizophrenia and Parkinson’s disease. In this study, we generate the functional antibody, which specifically recognizes DRD2, and we determined the ligand-free DRD2 structure using this antibody. This structure is believed to clarify the drug binding mechanism by comparison with already known antipsychotics binding structures. We also believe that it can help understand the mechanism of dopaminergic dysfunction.

Academic Significance and Societal Importance of the Research Achievements

脳神経疾患の治療薬の標的として最も重要なターゲットタンパク質の一つであるドパミン受容体の立体構造解明と向精神薬との結合様式の解明は、今後新たな薬剤の開発への展開ができることで社会に貢献すると期待される。

Research Products

• [Journal Article] Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA (2018)
  • Author(s): Suno Ryoji、Kimura Kanako Terakado、Nakane Takanori、Fujiwara Takaaki、Yamanaka Yasuaki、Im Dohyun、Rosenbaum Daniel M.、Iwata So、Shimamura Tatsuro、Kobayashi Takuya
  • Journal Title: Structure Volume: 26 Issue: 1 Pages: 7-19
  • DOI: 10.1016/j.str.2017.11.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ligand complex structures of L-amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 and its conformational change (2018)
  • Author(s): D. Im, D. Matsui, T. Arakawa, K. Isobe, Y. Asano, and S. Fushinobu
  • Journal Title: FEBS Open Bio Volume: 8(3) Issue: 3 Pages: 314-324
  • DOI: 10.1002/2211-5463.12387
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Structural insights into antipsychotics binding modes in dopamine D2-class receptors (2018)
  • Author(s): Dohyun Im, Yasuaki Yamanaka, Takaaki Fujiwara, Takanori Nakane, Tomoko Uemura, Chihiro Mori, Kanako Kimura, Eriko Nango, Kunio Hirata, Keitaro Yamashita, So Iwata and Tatsuro Shimamura
  • Organizer: Keystone Symposia: GPCR Structure and Function - Taking GPCR Drug Development and Discovery to the Next Level (Santa Fe, USA)
  • Int'l Joint Research
• [Presentation] A first novel GPCR structure determined at SACLA (2017)
  • Author(s): Dohyun Im, Tatsuro Shimamura, So Iwata
  • Organizer: 2017 International Symposium on Frontiers in structural biology for Drug Development (Pohang, Korea)
  • Int'l Joint Research / Invited