3DRU

Crystal Structure of Gly117Phe Alpha1-Antitrypsin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.242 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of alpha1-antitrypsin: implications for disease and drug design.

Gooptu, B.Miranda, E.Nobeli, I.Mallya, M.Purkiss, A.Brown, S.C.Summers, C.Phillips, R.L.Lomas, D.A.Barrett, T.E.

(2009) J Mol Biol 387: 857-868

  • DOI: https://doi.org/10.1016/j.jmb.2009.01.069
  • Primary Citation of Related Structures:  
    3DRM, 3DRU

  • PubMed Abstract: 

    The common Z mutant (Glu342Lys) of alpha(1)-antitrypsin results in the formation of polymers that are retained within hepatocytes. This causes liver disease whilst the plasma deficiency of an important proteinase inhibitor predisposes to emphysema. The Thr114Phe and Gly117Phe mutations border a surface cavity identified as a target for rational drug design. These mutations preserve inhibitory activity but reduce the polymerisation of wild-type native alpha(1)-antitrypsin in vitro and increase secretion in a Xenopus oocyte model of disease. To understand these effects, we have crystallised both mutants and solved their structures. The 2.2 A structure of Thr114Phe alpha(1)-antitrypsin demonstrates that the effects of the mutation are mediated entirely by well-defined partial cavity blockade and allows in silico screening of fragments capable of mimicking the effects of the mutation. The Gly117Phe mutation operates differently, repacking aromatic side chains in the helix F-beta-sheet A interface to induce a half-turn downward shift of the adjacent F helix. We have further characterised the effects of these two mutations in combination with the Z mutation in a eukaryotic cell model of disease. Both mutations increase the secretion of Z alpha(1)-antitrypsin in the native conformation, but the double mutants remain more polymerogenic than the wild-type (M) protein. Taken together, these data support different mechanisms by which the Thr114Phe and Gly117Phe mutations stabilise the native fold of alpha(1)-antitrypsin and increase secretion of monomeric protein in cell models of disease.


  • Organizational Affiliation

    School of Crystallography, Birkbeck College, University of London, London, UK. b.gooptu@mail.cryst.bbk.ac.uk


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Alpha-1-antitrypsin
A, B, C
404Homo sapiensMutation(s): 1 
Gene Names: SERPINA1AATPIPRO0684PRO2209
UniProt & NIH Common Fund Data Resources
Find proteins for P01009 (Homo sapiens)
Explore P01009 
Go to UniProtKB:  P01009
PHAROS:  P01009
GTEx:  ENSG00000197249 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01009
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.242 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.84α = 90
b = 149.3β = 94.11
c = 77.29γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
CNSrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references
  • Version 1.3: 2024-02-21
    Changes: Data collection