9KV6

Structure of mouse TLQP21 bound to mouse C3aR in complex with Go

9KV6 の概要

• エントリーDOI: 10.2210/pdb9kv6/pdb
• EMDBエントリー: 62586
• 分子名称: VGF-derived peptide TLQP-21, Muscarinic acetylcholine receptor M4,C3a anaphylatoxin chemotactic receptor, Guanine nucleotide-binding protein G(o) subunit alpha, ... (6 entities in total)
• 機能のキーワード: g protein coupled receptor, g protein, membrane protein, immunite system, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 163021.46

構造登録者

Banerjee, R.,Yadav, R.,Yadav, M.K.,Ganguly, M.,Mishra, S.,Dalal, A.,Gati, C.,Shukla, A.K. (登録日: 2024-12-04, 公開日: 2025-11-26)

主引用文献

Mishra, S.,Yadav, M.K.,Dalal, A.,Ganguly, M.,Yadav, R.,Sawada, K.,Tiwari, D.,Roy, N.,Banerjee, N.,Fung, J.N.,Marallag, J.,Cui, C.S.,Li, X.X.,Lee, J.D.,Dsouza, C.A.,Saha, S.,Sarma, P.,Rawat, G.,Zhu, H.,Khant, H.A.,Clark, R.J.,Sano, F.K.,Banerjee, R.,Woodruff, T.M.,Nureki, O.,Gati, C.,Shukla, A.K.
Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors.
Biorxiv, 2025

PubMed Abstract: Complement 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 βarr binding and activation using cryo-EM structures. Interestingly, we observe that βarrs 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.

PubMed: 40501890
DOI: 10.1101/2025.05.26.656101

実験手法

ELECTRON MICROSCOPY (2.88 Å)