5U00

CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH 3,3-difluoro-1-[(4-fluoro-3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.

Gomez, L.Massari, M.E.Vickers, T.Freestone, G.Vernier, W.Ly, K.Xu, R.McCarrick, M.Marrone, T.Metz, M.Yan, Y.G.Yoder, Z.W.Lemus, R.Broadbent, N.J.Barido, R.Warren, N.Schmelzer, K.Neul, D.Lee, D.Andersen, C.B.Sebring, K.Aertgeerts, K.Zhou, X.Tabatabaei, A.Peters, M.Breitenbucher, J.G.

(2017) J Med Chem 60: 2037-2051

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01793
  • Primary Citation of Related Structures:  
    5TZ3, 5TZA, 5TZC, 5TZH, 5TZW, 5TZX, 5TZZ, 5U00

  • PubMed Abstract: 

    A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.


  • Organizational Affiliation

    Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cGMP-dependent 3',5'-cyclic phosphodiesterase
A, B, C, D
344Homo sapiensMutation(s): 0 
Gene Names: PDE2A
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for O00408 (Homo sapiens)
Explore O00408 
Go to UniProtKB:  O00408
PHAROS:  O00408
GTEx:  ENSG00000186642 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00408
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7OV
Query on 7OV

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
[(5S)-3,3-difluoro-5-(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl](4-fluoro-3-iodophenyl)methanone
C18 H15 F3 I N5 O
BCKWAMYDZGLZLN-LBPRGKRZSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
O [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C],
P [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7OV Binding MOAD:  5U00 IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.986α = 109.38
b = 73.249β = 90.79
c = 91.206γ = 91.1
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
xia2data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-22
    Type: Initial release
  • Version 1.1: 2017-03-22
    Changes: Database references
  • Version 1.2: 2017-03-29
    Changes: Data collection
  • Version 1.3: 2017-11-22
    Changes: Refinement description
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references, Derived calculations