3U8D

Functionally selective inhibition of Group IIA phospholipase A2 reveals a role for vimentin in regulating arachidonic acid metabolism


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.121 
  • R-Value Observed: 0.126 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes.

Lee, L.K.Bryant, K.J.Bouveret, R.Lei, P.W.Duff, A.P.Harrop, S.J.Huang, E.P.Harvey, R.P.Gelb, M.H.Gray, P.P.Curmi, P.M.Cunningham, A.M.Church, W.B.Scott, K.F.

(2013) J Biol Chem 288: 15269-15279

  • DOI: https://doi.org/10.1074/jbc.M112.397893
  • Primary Citation of Related Structures:  
    3U8B, 3U8D, 3U8H, 3U8I

  • PubMed Abstract: 

    Human group IIA secreted phospholipase A2 (hGIIA) promotes tumor growth and inflammation and can act independently of its well described catalytic lipase activity via an alternative poorly understood signaling pathway. With six chemically diverse inhibitors we show that it is possible to selectively inhibit hGIIA signaling over catalysis, and x-ray crystal structures illustrate that signaling involves a pharmacologically distinct surface to the catalytic site. We demonstrate in rheumatoid fibroblast-like synoviocytes that non-catalytic signaling is associated with rapid internalization of the enzyme and colocalization with vimentin. Trafficking of exogenous hGIIA was monitored with immunofluorescence studies, which revealed that vimentin localization is disrupted by inhibitors of signaling that belong to a rare class of small molecule inhibitors that modulate protein-protein interactions. This study provides structural and pharmacological evidence for an association between vimentin, hGIIA, and arachidonic acid metabolism in synovial inflammation, avenues for selective interrogation of hGIIA signaling, and new strategies for therapeutic hGIIA inhibitor design.


  • Organizational Affiliation

    Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phospholipase A2, membrane associated
A, B
124Homo sapiensMutation(s): 0 
Gene Names: PLA2G2APLA2BPLA2LRASF-A
EC: 3.1.1.4
UniProt & NIH Common Fund Data Resources
Find proteins for P14555 (Homo sapiens)
Explore P14555 
Go to UniProtKB:  P14555
PHAROS:  P14555
GTEx:  ENSG00000188257 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14555
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
U8D
Query on U8D

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(3-{[3-(2-amino-2-oxoethyl)-1-benzyl-2-ethyl-1H-indol-5-yl]oxy}propyl)phosphonic acid
C22 H27 N2 O5 P
OPWQYOUZRHDKBR-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
I [auth B],
J [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
K [auth B],
L [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
U8D BindingDB:  3U8D IC50: min: 23, max: 9.11e+4 (nM) from 4 assay(s)
PDBBind:  3U8D IC50: 470 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.121 
  • R-Value Observed: 0.126 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.422α = 90
b = 74.422β = 90
c = 93.674γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
ADSCdata collection

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-17
    Type: Initial release
  • Version 1.1: 2013-06-12
    Changes: Database references
  • Version 1.2: 2019-07-17
    Changes: Advisory, Data collection, Refinement description