3EHU

Crystal structure of the extracellular domain of human corticotropin releasing factor receptor type 1 (CRFR1) in complex with CRF


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


This is version 2.2 of the entry. See complete history


Literature

Molecular Recognition of Corticotropin-releasing Factor by Its G-protein-coupled Receptor CRFR1.

Pioszak, A.A.Parker, N.R.Suino-Powell, K.Xu, H.E.

(2008) J Biol Chem 283: 32900-32912

  • DOI: https://doi.org/10.1074/jbc.M805749200
  • Primary Citation of Related Structures:  
    3EHS, 3EHT, 3EHU

  • PubMed Abstract: 

    The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.


  • Organizational Affiliation

    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. augie.pioszak@vai.org


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FUSION PROTEIN OF CRFR1 EXTRACELLULAR DOMAIN AND MBP
A, B
476Escherichia coli K-12Homo sapiens
This entity is chimeric
Mutation(s): 2 
UniProt & NIH Common Fund Data Resources
Find proteins for P0AEX9 (Escherichia coli (strain K12))
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Go to UniProtKB:  P0AEX9
Find proteins for P34998 (Homo sapiens)
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Go to UniProtKB:  P34998
PHAROS:  P34998
GTEx:  ENSG00000120088 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0AEX9P34998
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Corticoliberin
C, D
21Homo sapiensMutation(s): 0 
Gene Names: CRH
UniProt & NIH Common Fund Data Resources
Find proteins for P06850 (Homo sapiens)
Explore P06850 
Go to UniProtKB:  P06850
PHAROS:  P06850
GTEx:  ENSG00000147571 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06850
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose
E, F
2N/A
Glycosylation Resources
GlyTouCan:  G07411ON
GlyCosmos:  G07411ON
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.212 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.203α = 99.75
b = 63.48β = 106.28
c = 85.875γ = 101.67
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-09-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-08-02
    Changes: Refinement description, Source and taxonomy
  • Version 1.3: 2020-01-29
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2021-10-20
    Changes: Database references, Structure summary
  • Version 2.2: 2023-08-30
    Changes: Data collection, Refinement description