{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe motilin receptor (MLNR) is a class I G protein‐coupled receptor that mediates the actions of motilin—a peptide crucial for regulating gastrointestinal motility. Early structure–activity studies using truncated peptide fragments revealed that a minimal N‐terminal segment of motilin (approximately 14 amino acids) is required to fully activate the receptor, supporting the notion that a well‐conserved pharmacophore underlies MLNR function. In addition, these studies demonstrated that distinct chemical agonists—such as motilin and non‐peptidyl compounds like erythromycin—interact with different receptor regions, indicating that multiple binding sites on MLNR govern its activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDetailed mutagenesis experiments have further delineated the structural determinants of MLNR activity. Systematic substitutions and deletions in the extracellular loops, transmembrane domains, and intracellular loops have identified key amino acid residues that are essential for ligand binding, receptor activation, and G protein coupling. For instance, alterations in perimembranous regions and specific cysteine residues compromise ligand specificity and downstream calcium responses. These findings collectively suggest that MLNR activation is orchestrated by a complex interplay between its extracellular, transmembrane, and intracellular domains."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vivo investigations, including studies in human tissue and transgenic mouse models, have underlined the physiological and pathophysiological relevance of MLNR. Expression analyses show that MLNR is distributed in the gastrointestinal tract as well as in extra‐intestinal tissues—such as the thyroid and even the lacrimal gland—suggesting broader regulatory roles beyond gut motility. In disease models, alterations in MLNR expression or function have been linked to abnormal motility patterns and inflammatory states, while administration of motilin receptor agonists modulates gastric emptying and acyl-ghrelin levels, implying a compensatory relationship between motilin and ghrelin systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Leen Thielemans, Inge Depoortere, Jozef Vanden Broeck, et al. 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