Activation of the apelin receptor by the peptides apelin or Elabela/Toddler mediates vasodilatation and positive inotropic effects in the adult cardiovascular system and knocking out the receptors results in failure of the heart to develop in developing embryos. To date, only a limited number of Family A structures (including opioid, endothelin ETB, and orexin OX1 and OX2) have been deduced using X-ray crystallography. Ma et al., (2017) have recently reported the 2.6-Å resolution crystal structure of human apelin (APJ) receptor in complex with a synthetic 17-amino-acid apelin analogue agonist. The authors identify a two-site ligand binding mode that has not been seen in previous solved Family A receptor structures. The structure is in reasonable agreement with studies using NMR (Langelaan et al 2013) and molecular dynamics simulations (Macaluso and Glen 2010, Yang et al, 2017) In addition, many of the key interfacial receptor:agonist residues identified from the crystal structure are in agreement with mutation data on apelin binding. However, it is worth noting the following caveats that make interpretation of the data difficult:
1. Residues were removed from the N-terminus (residues 1–6) and C terminus (residues 331–380).
2. A putative glycosylation motif at N175 was eliminated from ECL2. It is an open question as to whether glycosylation affects agonist binding in the apelin receptor.
3. Two putative palmitoylation sites were removed from TM8. Again, it is an open question as to whether palmitoylation affects agonist binding in the apelin receptor.
4. To achieve crystallization, mutations V117A and W261K were introduced. These force the intracellular portion of the receptor into the inactive state. In fact, these mutations seem to render the receptor unable to bind apelin-13.
5. The synthetic 17-amino-acid apelin analogue agonist is significantly different from the apelin sequence. In particular, a macrocycle and significant mutations have been introduced, which may alter the peptide conformation and its interactions.
6. The crystal structure is unable to explain the importance of the Arg2 and Leu5 residues of apelin 13, which are known to be key binding elements from mutation data.
Despite these caveats, the crystal structure provides much needed data on the apelin receptor. A key question in the apelin field is why two peptides have evolved binding to the same ligand in mammals. Although the authors did not report binding with Elabela/Toddler analogues, the initial structure will foster understanding whether these two ligands differ in signalling mechanisms. Intriguingly, Lena et al (2017) have identified a key role for Elabela/Toddler in preeclampsia but this may not be mimicked by apelin suggesting spatiotemporal differences in signalling.
Comments by Anthony Davenport, David Huggins, Janet Maguire, and Robert Glen.
Ma et al. (2017) Structural Basis for Apelin Control of the Human Apelin Receptor. Structure. 6:858-866.e4. [PMID:28528775]
Langelaan et al. (2013) Structural features of the apelin receptor N-terminal tail and first transmembrane segment implicated in ligand binding and receptor trafficking. Biochim Biophys Acta. 1828:1471-83. [PMID:23438363]
Macaluso NJ, Glen RC. (2010) Exploring the ‘RPRL’ motif of apelin-13 through molecular simulation and biological evaluation of cyclic peptide analogues. ChemMedChem. 8:1247-53. [PMID:20486151]
Yang P et al. (2017) Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension. Circulation. [PMID:28137936]
Lena et al. (2017) ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science DOI. 10.1126/science.aam6607
guidetopharmacology blog 
Leave a Reply