4K5Y

Crystal structure of human corticotropin-releasing factor receptor 1 (CRF1R) in complex with the antagonist CP-376395


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.98 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.243 

Starting Models: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure of class B GPCR corticotropin-releasing factor receptor 1.

Hollenstein, K.Kean, J.Bortolato, A.Cheng, R.K.Dore, A.S.Jazayeri, A.Cooke, R.M.Weir, M.Marshall, F.H.

(2013) Nature 499: 438-443

  • DOI: https://doi.org/10.1038/nature12357
  • Primary Citation of Related Structures:  
    4K5Y

  • PubMed Abstract: 

    Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.


  • Organizational Affiliation

    Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticotropin-releasing factor receptor 1, T4-Lysozyme chimeric construct
A, B, C
441Homo sapiensTequatrovirus T4Mutation(s): 16 
Gene Names: CRF1RCRFRCRFR1CRHRCRHR1E
EC: 3.2.1.17
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Find proteins for P34998 (Homo sapiens)
Explore P34998 
Go to UniProtKB:  P34998
PHAROS:  P34998
GTEx:  ENSG00000120088 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P34998
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PGW
Query on PGW

Download Ideal Coordinates CCD File 
K [auth B],
L [auth B],
M [auth B]
(1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
C40 H77 O10 P
PAZGBAOHGQRCBP-HGWHEPCSSA-N
OLC
Query on OLC

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
J [auth B]
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
1Q5
Query on 1Q5

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B],
R [auth C]
3,6-dimethyl-N-(pentan-3-yl)-2-(2,4,6-trimethylphenoxy)pyridin-4-amine
C21 H30 N2 O
VIZBSVDBNLAVAW-UHFFFAOYSA-N
OLA
Query on OLA

Download Ideal Coordinates CCD File 
E [auth A],
S [auth C]
OLEIC ACID
C18 H34 O2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
N [auth B]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A],
O [auth B],
P [auth B],
Q [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
1Q5 PDBBind:  4K5Y Kd: 6.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.98 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.243 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.559α = 90
b = 123.968β = 90
c = 166.834γ = 90
Software Package:
Software NamePurpose
GDAdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
Aimlessdata 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: 2013-07-17
    Type: Initial release
  • Version 1.1: 2013-10-23
    Changes: Database references
  • Version 1.2: 2017-08-09
    Changes: Refinement description, Source and taxonomy
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description