PDBsum entry 6o3c

Signaling protein

PDB id: 6o3c

Contents

Protein chains

484 a.a.

122 a.a.

Ligands

PO4

OLB ×6

NAG ×2

LKD

CLR ×2

Metals

_NA

Waters ×3

PDB id:

6o3c

Name:

Signaling protein

Title:

Crystal structure of active smoothened bound to sag21k, cholesterol, and nbsmo8

Structure:

Smoothened homolog. Chain: a. Synonym: smo. Engineered: yes. Nbsmo8. Chain: b. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: smo, smoh. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293 gnti-. Expression_system_atcc_number: crl-3022. Synthetic: yes.

Resolution:

2.80Å R-factor: 0.248 R-free: 0.294

Authors:

I.S.Deshpande,J.Liang,D.Hedeen,K.J.Roberts,Y.Zhang,B.Ha, N.R.Latorraca,B.Faust,R.O.Dror,P.A.Beachy,B.R.Myers,A.Manglik

Key ref:

I.Deshpande et al. (2019). Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Nature, 571, 284-288. PubMed id: 31263273 DOI: 10.1038/s41586-019-1355-4

Date:

26-Feb-19 Release date: 03-Jul-19

Protein chain

P56726  (SMO_MOUSE) -  Protein smoothened from Mus musculus

Seq: 793 a.a.

Struc: 484 a.a.

Protein chain

No UniProt id for this chain

Struc: 122 a.a.

DOI no: 10.1038/s41586-019-1355-4

Nature 571:284-288 (2019)

PubMed id: 31263273

Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.

I.Deshpande, J.Liang, D.Hedeen, K.J.Roberts, Y.Zhang, B.Ha, N.R.Latorraca, B.Faust, R.O.Dror, P.A.Beachy, B.R.Myers, A.Manglik.

ABSTRACT

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration¹. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma². Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models^3-5, a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results-combined with signalling studies and molecular dynamics simulations-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.