6N2W

The structure of Stable-5-Lipoxygenase bound to NDGA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.71 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products.

Gilbert, N.C.Gerstmeier, J.Schexnaydre, E.E.Borner, F.Garscha, U.Neau, D.B.Werz, O.Newcomer, M.E.

(2020) Nat Chem Biol 16: 783-790

  • DOI: https://doi.org/10.1038/s41589-020-0544-7
  • Primary Citation of Related Structures:  
    6N2W, 6NCF

  • PubMed Abstract: 

    Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.


  • Organizational Affiliation

    Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Arachidonate 5-lipoxygenase
A, B
691Homo sapiensMutation(s): 0 
Gene Names: ALOX5LOG5
EC: 1.13.11.34 (PDB Primary Data), 1.13.11 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P09917 (Homo sapiens)
Explore P09917 
Go to UniProtKB:  P09917
PHAROS:  P09917
GTEx:  ENSG00000012779 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09917
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.71 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.152α = 90
b = 204.358β = 99.906
c = 76.712γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesR01HL107887
American Heart AssociationUnited States16GRNT31000010

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-13
    Type: Initial release
  • Version 1.1: 2020-05-27
    Changes: Database references
  • Version 1.2: 2020-07-08
    Changes: Database references
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description