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Journal articles

New structural insights into the apelin receptor: identification of key residues for apelin binding

Abstract : Apelin is the endogenous ligand of the orphan 7-transmembrane domain GPCR APJ, now named the apelin receptor (ApelinR). Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To better understand the structural organization of the ApelinR, we built 3 homology 3-dimensional (3D) models of the human ApelinR using the validated cholecystokinin receptor-1 3D model or the X-ray structures of the β2-adrenergic and CXCR4 receptors as templates. Docking of the pyroglutamyl form of apelin 13 (pE13F) into these models revealed the conservation at the bottom of the binding site of a hydrophobic cavity in which the C-terminal Phe of pE13F was embedded. In contrast, at the top of the binding site, depending on the model, different interactions were visualized between acidic residues of the ApelinR and the basic residues of pE13F. Using site-directed mutagenesis, we showed that Asp 92, Glu 172, and Asp 282 of rat ApelinR are key residues in apelin binding by interacting with Lys 8, Arg 2, and Arg 4 of pE13F, respectively. These residues are only seen in the CXCR4-based ApelinR 3D model, further validating this model. These findings bring new insights into the structural organization of the ApelinR and the mode of apelin binding.
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https://hal.inria.fr/hal-01251633
Contributor : David Ritchie Connect in order to contact the contributor
Submitted on : Wednesday, January 6, 2016 - 3:06:41 PM
Last modification on : Thursday, March 17, 2022 - 10:08:40 AM

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Romain Gerbier, Vincent Leroux, Pierre Couvineau, Rodrigo Alvear-Perez, Bernard Maigret, et al.. New structural insights into the apelin receptor: identification of key residues for apelin binding. FASEB Journal, Federation of American Society of Experimental Biology, 2015, 29 (1), pp.314-322. ⟨10.1096/fj.14-256339⟩. ⟨hal-01251633⟩

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