Crystal structures of human ET B receptor provide mechanistic insight into receptor activation and partial activation

Nat Commun. 2018 Nov 9;9(1):4711. doi: 10.1038/s41467-018-07094-0.

Abstract

Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signalling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ETB receptor in complex with ETB-selective agonist, endothelin-3 and an ETB-selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G-protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ETB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Endothelin-3 / metabolism
  • Endothelins / chemistry
  • Endothelins / metabolism
  • Endothelins / pharmacology
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Receptor, Endothelin B / agonists
  • Receptor, Endothelin B / chemistry*
  • Receptor, Endothelin B / metabolism*
  • Transforming Growth Factor alpha / metabolism
  • beta-Arrestins / metabolism

Substances

  • EDNRB protein, human
  • Endothelin-3
  • Endothelins
  • Mutant Proteins
  • Peptide Fragments
  • Receptor, Endothelin B
  • Transforming Growth Factor alpha
  • beta-Arrestins
  • IRL 1620