2. Academic Validation
  3. The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone

The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone

  • Structure. 2020 Apr 7;28(4):418-425.e4. doi: 10.1016/j.str.2019.12.003.
Hidetsugu Asada 1,  Asuka Inoue 2,  Francois Marie Ngako Kadji 3,  Kunio Hirata 4,  Yuki Shiimura 5,  Dohyun Im 6,  Tatsuro Shimamura 6,  Norimichi Nomura 6,  Hiroko Iwanari 7,  Takao Hamakubo 7,  Osamu Kusano-Arai 7,  Hiromi Hisano 6,  Tomoko Uemura 6,  Chiyo Suno 6,  Junken Aoki 8,  So Iwata 9
Affiliations

Affiliations

  • 1 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address: asada.hidetsugu.4s@kyoto-u.ac.jp.
  • 2 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan; Advanced Research & Development Programs for Medical Innovation (PRIME), Chiyoda, Tokyo 100-0004, Japan; Advanced Research & Development Programs for Medical Innovation (LEAP), Chiyoda, Tokyo 100-0004, Japan.
  • 3 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
  • 4 RIKEN, SPring-8 Center, Hyogo 679-5165, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Saitama 332-0012, Japan.
  • 5 Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka 830-0011, Japan.
  • 6 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • 7 Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
  • 8 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan; Advanced Research & Development Programs for Medical Innovation (LEAP), Chiyoda, Tokyo 100-0004, Japan.
  • 9 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; RIKEN, SPring-8 Center, Hyogo 679-5165, Japan. Electronic address: s.iwata@mfour.med.kyoto-u.ac.jp.
PMID: 31899086 DOI: 10.1016/j.str.2019.12.003
Abstract

Angiotensin II (AngII) is a peptide hormone that plays a key role in regulating blood pressure, and its interactions with the G protein-coupled receptors, AngII type-1 receptor (AT1R) and AngII type-2 receptor (AT2R), are central to its mechanism of action. We solved the crystal structure of human AT2R bound to AngII and its specific antibody at 3.2-Å resolution. AngII (full agonist) and [Sar1, Ile8]-AngII (partial agonist) interact with AT2R in a similar fashion, except at the bottom of the AT2R ligand-binding pocket. In particular, the residues including Met1283.36, which constitute the deep end of the cavity, play important roles in Angiotensin Receptor (ATR) activation upon AngII binding. These differences that occur upon endogenous ligand binding may contribute to a structural change in AT2R, leading to normalization of the non-canonical coordination of helix 8. Our results will inform the design of more effective ligands for ATRs.

Keywords

G protein coupled receptor; X-ray crystal structure; angiotensin receptor; peptide hormon.

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