Nov 2, 2018

Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500

BioRxiv : the Preprint Server for Biology
Chisae NagiriOsamu Nureki


Endothelin receptors (ETA and ETB) are G-protein coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 Angstrom-resolution. The structure revealed the different binding modes between IRL2500 and ET-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D2.50, stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.

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Mentioned in this Paper

Carboxy-Terminal Amino Acid
Blood Pressure Regulation
Antagonist Muscle Action
Integral to Membrane
Selenium and Vitamin E Efficacy Trial
Anatomical Space Structure

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