5L7D

Structure of human Smoothened in complex with cholesterol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 

Starting Model: experimental
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This is version 1.5 of the entry. See complete history


Literature

Structural basis of Smoothened regulation by its extracellular domains.

Byrne, E.F.Sircar, R.Miller, P.S.Hedger, G.Luchetti, G.Nachtergaele, S.Tully, M.D.Mydock-McGrane, L.Covey, D.F.Rambo, R.P.Sansom, M.S.Newstead, S.Rohatgi, R.Siebold, C.

(2016) Nature 535: 517-522

  • DOI: https://doi.org/10.1038/nature18934
  • Primary Citation of Related Structures:  
    5L7D, 5L7I

  • PubMed Abstract: 

    Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzledclass G-protein-coupled receptors (GPCRs) composed of both a heptahelical transmembrane domain (TMD) and an extracellular cysteine-rich domain (CRD). How the large extracellular domains of GPCRs regulate signalling by the TMD is unknown. We present crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains two distinct ligand-binding sites: one in its TMD and one in the CRD. The CRD is stacked a top the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations show that the interface between the CRD, linker domain and TMD stabilizes the inactive state of Smoothened. Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impair the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induces a conformational change that is propagated to the CRD, resulting in loss of cholesterol from the CRD-linker domain-TMD interface. Our results clarify the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains.


  • Organizational Affiliation

    Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Smoothened homolog,Soluble cytochrome b562,Smoothened homolog
A, B
638Homo sapiensEscherichia coliMutation(s): 0 
Gene Names: SMOSMOHcybC
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Find proteins for Q99835 (Homo sapiens)
Explore Q99835 
Go to UniProtKB:  Q99835
PHAROS:  Q99835
GTEx:  ENSG00000128602 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0ABE7Q99835
Glycosylation
Glycosylation Sites: 2Go to GlyGen: Q99835-1
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 122.9α = 90
b = 63.02β = 96.64
c = 208.59γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-20
    Type: Initial release
  • Version 1.1: 2016-08-03
    Changes: Database references
  • Version 1.2: 2016-08-10
    Changes: Database references
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 1.5: 2024-11-20
    Changes: Structure summary