6XBJ

Structure of human SMO-D384R complex with Gi

Summary for 6XBJ

• Entry DOI: 10.2210/pdb6xbj/pdb
• EMDB information: 22117
• Descriptor: 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)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 185947.37

Authors

Qi, X.,Long, T.,Li, X. (deposition date: 2020-06-06, release date: 2020-09-30, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.88 Å)