8DHA

Leptin-bound leptin receptor complex- focused interaction

8DHA の概要

• エントリーDOI: 10.2210/pdb8dha/pdb
• EMDBエントリー: 27434
• 分子名称: Leptin receptor, Leptin, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: leptin, receptor, complex, hormone
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 143351.75

構造登録者

Saxton, R.A.,Caveney, N.A.,Garcia, K.C. (登録日: 2022-06-25, 公開日: 2023-04-19, 最終更新日: 2025-05-21)

主引用文献

Saxton, R.A.,Caveney, N.A.,Moya-Garzon, M.D.,Householder, K.D.,Rodriguez, G.E.,Burdsall, K.A.,Long, J.Z.,Garcia, K.C.
Structural insights into the mechanism of leptin receptor activation.
Nat Commun, 14:1797-1797, 2023

PubMed Abstract: Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

PubMed: 37002197
DOI: 10.1038/s41467-023-37169-6

実験手法

ELECTRON MICROSCOPY (3.8 Å)