9V4D

Structure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 bound to R8Y

9V4D の概要

• エントリーDOI: 10.2210/pdb9v4d/pdb
• EMDBエントリー: 64777
• 分子名称: C5a anaphylatoxin chemotactic receptor 2, R8Y ligand (2 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: 2
• 化学式量合計: 42965.93

構造登録者

Tiwari, D.,Sano, F.K.,Yadav, M.K.,Sawada, K.,Ganguly, M.,Mishra, S.,Dalal, A.,Banerjee, R.,Nureki, O.,Shukla, A.K. (登録日: 2025-05-23, 公開日: 2026-07-01)

主引用文献

Tiwari, D.,Sawada, K.,Dalal, A.,Mishra, S.,Li, X.X.,Dent, J.C.,Kim, K.,Yadav, M.K.,Roy, N.,Ganguly, M.,Banerjee, N.,Stepniewski, T.M.,Ahn, D.,Yamaguchi, K.,Oshima, H.S.,Hashimoto, K.,Fung, J.N.,Lerskiatiphanich, T.,Cui, C.S.,Lee, J.D.,Selent, J.,Inoue, A.,Clark, R.J.,Chung, K.Y.,Banerjee, R.,Sano, F.K.,Woodruff, T.M.,Nureki, O.,Shukla, A.K.
Molecular mechanisms of naturally encoded signaling bias at the complement anaphylatoxin receptors.
Mol.Cell, 2026

PubMed Abstract: The conceptual framework of biased agonism has greatly impacted our understanding of G-protein-coupled receptor (GPCR) signaling, regulatory paradigms, and drug discovery efforts. Here, we present fundamental molecular and structural insights into intrinsic bias encoded at the human and mouse complement anaphylatoxin C5a receptors, namely C5aR1 and C5aR2. We discover that a naturally occurring version of C5a, i.e., C5a, exhibits a robust G-protein-coupling bias at C5aR1 with attenuated β-arrestin (βarr) recruitment, which originates from a distinct conformation of TM7 and helix 8 in the receptor, leading to inefficient GRK recruitment and phosphorylation. We also determine a series of cryo-electron microscopy (cryo-EM) structures of C5aR2, a naturally encoded βarr-biased receptor, which uncover key differences in anaphylatoxin recognition by C5aR2 relative to C5aR1. These structural snapshots also uncover a shallower cytoplasmic pocket in C5aR2 with a hydrophobic interior, which is likely incompatible with efficient G-protein coupling, leading to intrinsic bias. Our findings illuminate the molecular basis of naturally encoded signaling bias at GPCRs, with direct implications for therapeutic design.

PubMed: 42330960
DOI: 10.1016/j.molcel.2026.06.002

実験手法

ELECTRON MICROSCOPY (3.07 Å)