5BJT

Crystal structure of human FcRn with a peptide inhibitor at multiple sites


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.339 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.257 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

Pyzik, M.Rath, T.Kuo, T.T.Win, S.Baker, K.Hubbard, J.J.Grenha, R.Gandhi, A.Kramer, T.D.Mezo, A.R.Taylor, Z.S.McDonnell, K.Nienaber, V.Andersen, J.T.Mizoguchi, A.Blumberg, L.Purohit, S.Jones, S.D.Christianson, G.Lencer, W.I.Sandlie, I.Kaplowitz, N.Roopenian, D.C.Blumberg, R.S.

(2017) Proc Natl Acad Sci U S A 114: E2862-E2871

  • DOI: https://doi.org/10.1073/pnas.1618291114
  • Primary Citation of Related Structures:  
    5BJT

  • PubMed Abstract: 

    The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.


  • Organizational Affiliation

    Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
IgG receptor FcRn large subunit p51
A, C, E, G
267Homo sapiensMutation(s): 0 
Gene Names: FCGRTFCRN
UniProt & NIH Common Fund Data Resources
Find proteins for P55899 (Homo sapiens)
Explore P55899 
Go to UniProtKB:  P55899
PHAROS:  P55899
GTEx:  ENSG00000104870 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55899
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulin
B, D, F, H
99Homo sapiensMutation(s): 0 
Gene Names: B2MCDABP0092HDCMA22P
UniProt & NIH Common Fund Data Resources
Find proteins for P61769 (Homo sapiens)
Explore P61769 
Go to UniProtKB:  P61769
PHAROS:  P61769
GTEx:  ENSG00000166710 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61769
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
peptide inhibitor19synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.339 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.257 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.917α = 90
b = 176.152β = 90
c = 245.515γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
REFMACrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-22
    Type: Initial release
  • Version 1.1: 2017-04-05
    Changes: Database references
  • Version 1.2: 2017-04-19
    Changes: Database references
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description