5AE2

Ether Lipid-Generating Enzyme AGPS in complex with inhibitor 1e


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Inhibitors for the Ether Lipid-Generating Enzyme Agps as Anti-Cancer Agents.

Piano, V.Benjamin, D.I.Valente, S.Nenci, S.Marrocco, B.Mai, A.Aliverti, A.Nomura, D.K.Mattevi, A.

(2015) ACS Chem Biol 10: 2589-2597

  • DOI: https://doi.org/10.1021/acschembio.5b00466
  • Primary Citation of Related Structures:  
    5ADZ, 5AE1, 5AE2, 5AE3

  • PubMed Abstract: 

    Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors. We have identified several lead AGPS inhibitors and have structurally characterized their interactions with the enzyme and show that these inhibitors bind to distinct portions of the active site. We further show that the lead AGPS inhibitor 1a selectively lowers ether lipid levels in several types of human cancer cells and impairs their cellular survival and migration. We provide here the first report of in situ-active pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy.


  • Organizational Affiliation

    Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALKYLDIHYDROXYACETONEPHOSPHATE SYNTHASE, PEROXISOMAL
A, B, C, D
658Cavia porcellusMutation(s): 0 
UniProt
Find proteins for P97275 (Cavia porcellus)
Explore P97275 
Go to UniProtKB:  P97275
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP97275
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
O [auth D]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
FYC
Query on FYC

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
3-(2-fluorophenyl)-2-methyl-N-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)acrylamide
C18 H16 F N3 O2
MNPHMLQQNDWSRS-DHZHZOJOSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C],
P [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.53α = 90.57
b = 98.57β = 90.14
c = 107.07γ = 95.67
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-09
    Type: Initial release
  • Version 1.1: 2015-12-02
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description