9kv6
Structure of mouse TLQP21 bound to mouse C3aR in complex with Go
Structural highlights
FunctionVGF_MOUSE Secreted polyprotein that is packaged and proteolytically processed by prohormone convertases PCSK1 and PCSK2 in a cell-type-specific manner (By similarity). VGF and peptides derived from its processing play many roles in neurogenesis and neuroplasticity associated with learning, memory, depression and chronic pain (PubMed:19863797, PubMed:26180209, PubMed:30504797).[UniProtKB:P20156][1] [2] [3] Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Suppresses presynaptic glutamatergic neurons connected to vasopressin neurons.[UniProtKB:P20156] Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Activates GABAergic interneurons which are inhibitory neurons of the nervous system and thereby suppresses presynaptic glutamatergic neurons (By similarity). Also stimulates feeding behavior in an orexin-dependent manner in the hypothalamus (By similarity). Functions as a positive regulator for the activation of orexin neurons resulting in elevated gastric acid secretion and gastric emptying (By similarity).[UniProtKB:P20156] Secreted multifunctional peptide that interacts with different receptors and thereby plays multiple physiological roles including modulation of energy expenditure, pain, response to stress, gastric regulation as well as lipolysis (PubMed:22289198, PubMed:25456411). Activates the G-protein-coupled receptor C3AR1 via a folding-upon-binding mechanism leading to enhanced lipolysis in adipocytes (PubMed:25456411). Interacts with gC1qR receptor in macrophages and microglia causing increased levels of intracellular calcium and hypersensitivity (By similarity).[UniProtKB:P20156][4] [5] Plays a role in the regulation of memory formation and depression-related behaviors potentially by influencing synaptic plasticity and neurogenesis. Induces acute and transient activation of the NTRK2/TRKB receptor and subsequent CREB phosphorylation (PubMed:26180209, PubMed:30504797). Also induces insulin secretion in insulinoma cells by increasing intracellular calcium mobilization (PubMed:25917832).[6] [7] [8] Publication Abstract from PubMedComplement anaphylatoxin receptors (C3aR and C5aR1) are prototypical G protein-coupled receptors (GPCRs) playing crucial physiological roles in innate immunity by combating pathogenic infections and orchestrating inflammatory responses. They continue to be important therapeutic targets for multiple disorders including autoimmune diseases, acute and chronic inflammation, and allergy-related conditions. Recent structural coverage has provided important insights into their activation and signaling, however, confounding observations in the literature related to ligand efficacy and functional responses, especially in different model systems, present a major challenge for drug discovery efforts. Here, we systematically and comprehensively profile a broad set of natural and synthetic ligands at C3aR and C5aR1 and discover a previously unanticipated level of functional specialization in terms of species-specific pharmacology and receptor activation. Taking a lead from this, we determine seventeen cryo-EM structures of different ligand-receptor-G-protein complexes and uncover distinct orientation of agonists between the human and mouse receptors despite an overlapping positioning in the orthosteric binding pocket. Combined with extensive mutagenesis and functional assays, these structural snapshots allow us to decode and validate a convergent molecular mechanism involving a "Five-Point-Switch" in these receptors that orchestrates the recognition and efficacy of diverse agonists. We also identify species-specific differences at the level of phosphorylation patterns encoded in the carboxyl-terminus of these receptors and directly visualize their impact on betaarr binding and activation using cryo-EM structures. Interestingly, we observe that betaarrs engage with the mouse C5aR1 using a variation of previously discovered P-X-P-P phosphorylation motif via a "Sliding-Mechanism" and also exhibit distinct oligomeric state for the human vs. mouse receptors. Taken together, this study elucidates functional specialization at the complement anaphylatoxin receptors and underlying molecular mechanisms, offering a previously lacking framework with direct and immediate implications for the development of novel therapeutics. Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors.,Mishra S, Yadav MK, Dalal A, Ganguly M, Yadav R, Sawada K, Tiwari D, Roy N, Banerjee N, Fung JN, Marallag J, Cui CS, Li XX, Lee JD, Dsouza CA, Saha S, Sarma P, Rawat G, Zhu H, Khant HA, Clark RJ, Sano FK, Banerjee R, Woodruff TM, Nureki O, Gati C, Shukla AK bioRxiv [Preprint]. 2025 May 29:2025.05.26.656101. doi: , 10.1101/2025.05.26.656101. PMID:40501890[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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