3CHQ

Crystal structure of leukotriene a4 hydrolase in complex with N5-[4-(phenylmethoxy)phenyl]-L-glutamine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.206 

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This is version 1.3 of the entry. See complete history


Literature

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

Kirkland, T.A.Adler, M.Bauman, J.G.Chen, M.Haeggstrom, J.Z.King, B.Kochanny, M.J.Liang, A.M.Mendoza, L.Phillips, G.B.Thunnissen, M.Trinh, L.Whitlow, M.Ye, B.Ye, H.Parkinson, J.Guilford, W.J.

(2008) Bioorg Med Chem 16: 4963-4983

  • DOI: https://doi.org/10.1016/j.bmc.2008.03.042
  • Primary Citation of Related Structures:  
    3CHO, 3CHP, 3CHQ, 3CHR, 3CHS

  • PubMed Abstract: 

    Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. Thomas.kirkland@promega.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Leukotriene A-4 hydrolase610Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
4BQ PDBBind:  3CHQ IC50: 20 (nM) from 1 assay(s)
Binding MOAD:  3CHQ IC50: 20 (nM) from 1 assay(s)
BindingDB:  3CHQ IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.206 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.234α = 90
b = 133.262β = 90
c = 84.591γ = 90
Software Package:
Software NamePurpose
CNXrefinement
MOSFLMdata reduction
SCALAdata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2019-11-20
    Changes: Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations