3FTW

Leukotriene A4 hydrolase in complex with fragments N-(pyridin-3-ylmethyl)aniline and acetate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.

Davies, D.R.Mamat, B.Magnusson, O.T.Christensen, J.Haraldsson, M.H.Mishra, R.Pease, B.Hansen, E.Singh, J.Zembower, D.Kim, H.Kiselyov, A.S.Burgin, A.B.Gurney, M.E.Stewart, L.J.

(2009) J Med Chem 52: 4694-4715

  • DOI: https://doi.org/10.1021/jm900259h
  • Primary Citation of Related Structures:  
    3FTS, 3FTU, 3FTV, 3FTW, 3FTX, 3FTY, 3FU0, 3FU3, 3FU5, 3FU6, 3FUD, 3FUE, 3FUF, 3FUH, 3FUI, 3FUJ, 3FUK, 3FUM, 3FUN

  • PubMed Abstract: 

    We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.


  • Organizational Affiliation

    deCODE biostructures, Inc., 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Leukotriene A-4 hydrolase611Homo sapiensMutation(s): 0 
Gene Names: LTA4HLTA4
EC: 3.3.2.6
UniProt & NIH Common Fund Data Resources
Find proteins for P09960 (Homo sapiens)
Explore P09960 
Go to UniProtKB:  P09960
PHAROS:  P09960
GTEx:  ENSG00000111144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09960
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
11X
Query on 11X

Download Ideal Coordinates CCD File 
D [auth A]N-(pyridin-3-ylmethyl)aniline
C12 H12 N2
BJXLHKJBRORJJJ-UHFFFAOYSA-N
YB
Query on YB

Download Ideal Coordinates CCD File 
C [auth A]YTTERBIUM (III) ION
Yb
AWSFICBXMUKWSK-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
11X PDBBind:  3FTW IC50: 1.67e+6 (nM) from 1 assay(s)
BindingDB:  3FTW IC50: min: 1.32e+6, max: 1.67e+6 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.311α = 90
b = 86.952β = 90
c = 99.528γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-07-28 
  • Deposition Author(s): Davies, D.R.

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description