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The human receptor contains a conserved disulfide bridge linking the N\u2010terminal domain to extracellular loop 3 (ECL3) via Cys19 and Cys281, forming a structural constraint analogous to a fourth extracellular loop (\u2018ECL4\u2019). In the chemokine receptor family, this motif plays a critical role in ligand engagement and receptor activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The functional role of this disulfide bridge was investigated using site\u2010directed mutagenesis (Cys19Ala and Cys281Ala), plasmon waveguide resonance binding assays and BRET\u2010based biosensors to monitor G\n                      <jats:italic>\u03b1<\/jats:italic>\n                      i activation and\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010arrestin\u20102 recruitment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Disruption of the disulfide bridge did not affect receptor surface expression but markedly impaired binding of apelin fragments (pE13F and K17F), leading to reduced G\n                      <jats:italic>\u03b1<\/jats:italic>\n                      i signalling and\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010arrestin\u20102 recruitment. In contrast, binding of the Elabela fragment K22P and the subsequent apelin receptor signalling activation were largely preserved. Antagonist antibodies (JN241 and JN241\u2010Fc) retained activity, whereas the agonist antibody JN241\u20109\u2010Fc showed strongly reduced efficacy for the mutated receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The N\u2010terminal\/ECL3 disulfide bridge is a critical structural determinant for apelin binding and apelin receptor activation but is less critical for Elabela signalling, supporting distinct modes of ligand engagement. Antibody\u2010mediated agonism is particularly sensitive to alterations of \u00ab ECL4 \u00bb without affecting its binding, suggesting that this structural constraint is required for optimal apelin receptor activation. The apelin receptor shares functional similarities with the chemokine receptors with respect to this.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70558","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:06:33Z","timestamp":1783134393000},"page":"5641-5656","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The chemokine receptor\u2010like fourth extracellular loop of the apelin receptor differentially regulates apelin and elabela binding and signalling"],"prefix":"10.1111","volume":"183","author":[{"given":"Chlo\u00e9","family":"Bonef","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay, CEA, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Service d'Ing\u00e9nierie Mol\u00e9culaire pour la Sant\u00e9 (SIMoS), EMR CNRS  Gif\u2010sur\u2010Yvette 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