The apelin receptor (the angiotensin receptor like-1, the angiotensin II protein J receptor or APJR) is a member of the class A G protein-coupled receptors (GPCRs). APJR plays an important role in diverse (patho)physiological functions such as angiogenesis, vasoconstriction, heart muscle contractility, regulation of energy metabolism, and fluid homeostasis. After its cloning in 1993, the first endogenous peptide agonist apelin was identified, followed by the recent discovery of its second endogenous ligand Elabela (ELA)/Toddler/Apela. Both series of endogenous peptide ligands of APJR vary in length and amino acid sequence. However, previous studies reported that they occupy the same orthosteric binding site and share similar functional activities and signaling mechanisms. The therapeutic potential of APJR agonists for cardiac diseases was demonstrated by the acute administration of apelin in heart failure patients. Thus, there is growing interest in the pharmaceutical industry to discover novel APJR agonists as potential treatments for heart failure. In order to understand the fundamental biology and facilitate drug discovery, we embarked on an effort to gain structural insights into the molecular basis of APJR-peptide recognition and receptor signal transduction. Herein we report the high resolution co-crystal structure of human APJR in complex with a designed apelin-17 mimetic peptide. Overall structural features of the complex and detailed interactions between the ligand and the receptor will be described. Mutational studies that led to deeper understanding of receptor signaling will also be discussed.

High resolution co-crystal structure of the apelin receptor and peptide agonist complex

254th National Meeting (2017)

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