3C4M

Structure of human parathyroid hormone in complex with the extracellular domain of its G-protein-coupled receptor (PTH1R)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

Molecular recognition of parathyroid hormone by its G protein-coupled receptor.

Pioszak, A.A.Xu, H.E.

(2008) Proc Natl Acad Sci U S A 105: 5034-5039

  • DOI: https://doi.org/10.1073/pnas.0801027105
  • Primary Citation of Related Structures:  
    3C4M

  • PubMed Abstract: 

    Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-A structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer alpha-beta-betaalpha fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.


  • Organizational Affiliation

    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503, USA


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fusion protein of Maltose-binding periplasmic protein and Parathyroid hormone/parathyroid hormone-related peptide receptor
A, B
539Escherichia coliHomo sapiens
This entity is chimeric
Mutation(s): 0 
Gene Names: malEPTHR1PTHR
UniProt & NIH Common Fund Data Resources
Find proteins for P0AEX9 (Escherichia coli (strain K12))
Explore P0AEX9 
Go to UniProtKB:  P0AEX9
Find proteins for Q03431 (Homo sapiens)
Explore Q03431 
Go to UniProtKB:  Q03431
PHAROS:  Q03431
GTEx:  ENSG00000160801 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0AEX9Q03431
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Parathyroid hormone
C, D
21Homo sapiensMutation(s): 0 
Gene Names: PTH
UniProt & NIH Common Fund Data Resources
Find proteins for P01270 (Homo sapiens)
Explore P01270 
Go to UniProtKB:  P01270
PHAROS:  P01270
GTEx:  ENSG00000152266 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01270
Sequence Annotations
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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: 1.95 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.919α = 90
b = 116.791β = 108.8
c = 78.416γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection
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: 2008-04-08
    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 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-08-30
    Changes: Data collection, Database references, Refinement description, Structure summary