Hello. My name is Tomoko Doi from Kyoto University.
In this seminar, I would like to present the
structures and activation of Endothelin,
ETB receptor by Endothelin.
In this presentation, firstly,
I will provide some brief background about the Endothelin system.
Secondly, I will describe the features of thermostabilized Endothelium receptor type B,
abbreviated as ETB, which we developed for crystallization.
Thirdly, I will present the structures of ETB in the ligand-free form,
bound to its agonist ET1, and bound to the antagonist Bosentan.
Finally, I will compare these structures to discuss how
the ETB receptor changes its conformation upon the binding of the agonist ET1.
In mammals, the Endothelin,
ET family comprises of three endogenous isoforms: ET1,
ET2, and ET3 found by Yanagisawa and colleagues.
They are each 21 amino acid residues long and they have
unique cyclic structures with two intramolecular disulfide bonds.
ET2 and ET3 have high sequence similarity to ET1, especially in residues 8-21.
ET1, the principle isoform in the human cardiovascular system,
is one of the most abundant,
potent, and long-lasting constrictors of human vessels.
Constriction is needed by ET receptors in smooth muscle cells;
whereas, ET receptors in endothelial cells limit
the constrictor response by releasing basal dilators such as nitric oxide.
These responses coordinate and thus, regulate local vascular tone.
There are two subtypes of ET receptors:
type A and type B,
abbreviated as ETA and ETB.
Both subtypes are GPCRs,
smooth muscle cells express both types,
while vascular endothelial cells express mostly ETB.
A number of studies have demonstrated that ET1 is