8AVE

Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric isoleucine GCN4 zipper (2:2 model)

8AVE の概要

• エントリーDOI: 10.2210/pdb8ave/pdb
• 関連するPDBエントリー: 7z3q 7z3r
• EMDBエントリー: 15680
• 分子名称: Leptin, Leptin receptor (2 entities in total)
• 機能のキーワード: leptin, lep-r, obesity, metabolism, energy balance, cytokine
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 234854.25

構造登録者

Verstraete, K.,Savvides, S.N.,Verschueren, K.G.,Tsirigotaki, A. (登録日: 2022-08-26, 公開日: 2023-04-05, 最終更新日: 2024-10-23)

主引用文献

Tsirigotaki, A.,Dansercoer, A.,Verschueren, K.H.G.,Markovic, I.,Pollmann, C.,Hafer, M.,Felix, J.,Birck, C.,Van Putte, W.,Catteeuw, D.,Tavernier, J.,Fernando Bazan, J.,Piehler, J.,Savvides, S.N.,Verstraete, K.
Mechanism of receptor assembly via the pleiotropic adipokine Leptin.
Nat.Struct.Mol.Biol., 30:551-563, 2023

PubMed Abstract: The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.

PubMed: 36959263
DOI: 10.1038/s41594-023-00941-9

実験手法

ELECTRON MICROSCOPY (5.62 Å)