PDBsum entry 6xbl

Membrane protein

PDB id: 6xbl

Contents

Protein chains

468 a.a.

215 a.a.

336 a.a.

53 a.a.

232 a.a.

Ligands

V0S

CLR

PDB id:

6xbl

Name:

Membrane protein

Title:

Structure of human smo-gi complex with sag

Structure:

Smoothened homolog. Chain: r. Synonym: smo,protein gx. Engineered: yes. Guanine nucleotide-binding protein g(i) subunit alpha-1. Chain: a. Synonym: adenylate cyclase-inhibiting g alpha protein. Engineered: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(t) subunit

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: smo, smoh. Expressed in: homo sapiens. Expression_system_taxid: 9606. Gene: gnai1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.

Authors:

X.Qi,X.Li

Key ref:

X.Qi et al. (2020). Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling. Nat Chem Biol, 16, 1368-1375. PubMed id: 32929279 DOI: 10.1038/s41589-020-0646-2

Date:

06-Jun-20 Release date: 30-Sep-20

Protein chain

Q99835  (SMO_HUMAN) -  Protein smoothened from Homo sapiens

Seq: 787 a.a.

Struc: 468 a.a.

Protein chain

P63096  (GNAI1_HUMAN) -  Guanine nucleotide-binding protein G(i) subunit alpha-1 from Homo sapiens

Seq: 354 a.a.

Struc: 215 a.a.

Protein chain

P62873  (GBB1_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Homo sapiens

Seq: 340 a.a.

Struc: 336 a.a.

Protein chain

P59768  (GBG2_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 from Homo sapiens

Seq: 71 a.a.

Struc: 53 a.a.

Protein chain

No UniProt id for this chain

Struc: 232 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.3.6.5.- - ?????

DOI no: 10.1038/s41589-020-0646-2

Nat Chem Biol 16:1368-1375 (2020)

PubMed id: 32929279

Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.

X.Qi, L.Friedberg, R.De Bose-Boyd, T.Long, X.Li.

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_i 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^D384R and SMO^G111C/I496C, 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.