6XBM

Structure of human SMO-Gi complex with 24(S),25-EC

6XBM の概要

• エントリーDOI: 10.2210/pdb6xbm/pdb
• EMDBエントリー: 22120
• 分子名称: Smoothened homolog, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• 機能のキーワード: gpcr, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 186319.88

構造登録者

Qi, X.,Long, T.,Li, X. (登録日: 2020-06-06, 公開日: 2020-09-30, 最終更新日: 2024-10-09)

主引用文献

Qi, X.,Friedberg, L.,De Bose-Boyd, R.,Long, T.,Li, X.
Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.
Nat.Chem.Biol., 16:1368-1375, 2020

PubMed Abstract: Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-G complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMO and SMO, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.

PubMed: 32929279
DOI: 10.1038/s41589-020-0646-2

実験手法

ELECTRON MICROSCOPY (3.14 Å)