4S0V

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug Suvorexant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant.

Yin, J.Mobarec, J.C.Kolb, P.Rosenbaum, D.M.

(2015) Nature 519: 247-250

  • DOI: https://doi.org/10.1038/nature14035
  • Primary Citation of Related Structures:  
    4S0V

  • PubMed Abstract: 

    The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.


  • Organizational Affiliation

    Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Human Orexin receptor type 2 fusion protein to P. abysii Glycogen Synthase559Homo sapiensPyrococcus abyssi GE5Mutation(s): 0 
Gene Names: HCRTR2PAB2292PYRAB00770
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9V2J8 (Pyrococcus abyssi (strain GE5 / Orsay))
Explore Q9V2J8 
Go to UniProtKB:  Q9V2J8
Find proteins for O43614 (Homo sapiens)
Explore O43614 
Go to UniProtKB:  O43614
PHAROS:  O43614
GTEx:  ENSG00000137252 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsQ9V2J8O43614
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SUV
Query on SUV

Download Ideal Coordinates CCD File 
B [auth A][(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
C23 H23 Cl N6 O2
JYTNQNCOQXFQPK-MRXNPFEDSA-N
OLA
Query on OLA

Download Ideal Coordinates CCD File 
C [auth A]OLEIC ACID
C18 H34 O2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SUV BindingDB:  4S0V Ki: min: 0.35, max: 12 (nM) from 5 assay(s)
IC50: min: 0.4, max: 138 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.358α = 90
b = 75.819β = 111.71
c = 96.335γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-14
    Type: Initial release
  • Version 1.1: 2015-03-18
    Changes: Database references
  • Version 1.2: 2015-03-25
    Changes: Database references
  • Version 1.3: 2017-08-23
    Changes: Refinement description, Source and taxonomy
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description