5V18

Structure of PHD2 in complex with 1,2,4-Triazolo-[1,5-a]pyridine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.

Ahmed, S.Ayscough, A.Barker, G.R.Canning, H.E.Davenport, R.Downham, R.Harrison, D.Jenkins, K.Kinsella, N.Livermore, D.G.Wright, S.Ivetac, A.D.Skene, R.Wilkens, S.J.Webster, N.A.Hendrick, A.G.

(2017) J Med Chem 60: 5663-5672

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00352
  • Primary Citation of Related Structures:  
    5V18, 5V1B

  • PubMed Abstract: 

    Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe 2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.


  • Organizational Affiliation

    Department of Computational Sciences and Crystallography, Takeda California Inc. , 10410 Science Center Dr., San Diego, California 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Egl nine homolog 1239Homo sapiensMutation(s): 0 
Gene Names: EGLN1C1orf12PNAS-118PNAS-137
EC: 1.14.11.29
UniProt & NIH Common Fund Data Resources
Find proteins for Q9GZT9 (Homo sapiens)
Explore Q9GZT9 
Go to UniProtKB:  Q9GZT9
PHAROS:  Q9GZT9
GTEx:  ENSG00000135766 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9GZT9
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.528α = 90
b = 72.528β = 90
c = 45.642γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-06-21 
  • Deposition Author(s): Skene, R.J.

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-21
    Type: Initial release
  • Version 1.1: 2017-07-26
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations