6wzg
Human secretin receptor Gs complex
Structural highlights
FunctionSECR_HUMAN Hormone involved in different processes, such as regulation of the pH of the duodenal content, food intake and water homeostasis (PubMed:25332973). Exerts its biological effects by binding to secretin receptor (SCTR), a G-protein coupled receptor expressed in the basolateral domain of several cells (PubMed:25332973). Acts as a key gastrointestinal hormone by regulating the pH of the duodenal content (By similarity). Secreted by S cells of the duodenum in the crypts of Lieberkuehn and regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas (By similarity). Production of bicarbonate is essential to neutralize the pH and ensure no damage is done to the small intestine by the gastric acid (By similarity). In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation (Probable). Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation (By similarity). Also able to stimulate lipolysis in white adipocytes (By similarity). Also plays an important role in cellular osmoregulation: released into the systemic circulation in response to hyperosmolality and acts at different levels in the hypothalamus, pituitary and kidney to regulate water homeostasis (By similarity). Also plays a role in the central nervous system, possibly by acting as a neuropeptide hormone: required for hippocampal synaptic function and neural progenitor cells maintenance (By similarity).[UniProtKB:P11384][UniProtKB:Q08535][1] [2] Publication Abstract from PubMedThe class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 A structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD. Structure and dynamics of the active Gs-coupled human secretin receptor.,Dong M, Deganutti G, Piper SJ, Liang YL, Khoshouei M, Belousoff MJ, Harikumar KG, Reynolds CA, Glukhova A, Furness SGB, Christopoulos A, Danev R, Wootten D, Sexton PM, Miller LJ Nat Commun. 2020 Aug 18;11(1):4137. doi: 10.1038/s41467-020-17791-4. PMID:32811827[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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