3ZNN

IN VITRO AND IN VIVO INHIBITION OF HUMAN D-AMINO ACID OXIDASE: REGULATION OF D-SERINE CONCENTRATION IN THE BRAIN


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural, Kinetic, and Pharmacodynamic Mechanisms of D-Amino Acid Oxidase Inhibition by Small Molecules.

Hopkins, S.C.Heffernan, M.L.R.Saraswat, L.D.Bowen, C.A.Melnick, L.Hardy, L.W.Orsini, M.A.Allen, M.S.Koch, P.Spear, K.L.Foglesong, R.J.Soukri, M.Chytil, M.Fang, Q.K.Jones, S.W.Varney, M.A.Panatier, A.Oliet, S.H.R.Pollegioni, L.Piubelli, L.Molla, G.Nardini, M.Large, T.H.

(2013) J Med Chem 56: 3710

  • DOI: https://doi.org/10.1021/jm4002583
  • Primary Citation of Related Structures:  
    3ZNN, 3ZNO, 3ZNP, 3ZNQ

  • PubMed Abstract: 

    We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.


  • Organizational Affiliation

    Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts 01752, United States. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
D-AMINO-ACID OXIDASE
A, B
347Homo sapiensMutation(s): 0 
EC: 1.4.3.3
UniProt & NIH Common Fund Data Resources
Find proteins for P14920 (Homo sapiens)
Explore P14920 
Go to UniProtKB:  P14920
PHAROS:  P14920
GTEx:  ENSG00000110887 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14920
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
C [auth A],
L [auth B]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
4WL
Query on 4WL

Download Ideal Coordinates CCD File 
D [auth A],
M [auth B]
4H-THIENO[3,2-B]PYROLE-5-CARBOXYLIC ACID
C7 H5 N O2 S
PMHDSACGRKBACK-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
N [auth B],
O [auth B],
P [auth B],
Q [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4WL BindingDB:  3ZNN Ki: 3.5 (nM) from 1 assay(s)
Kd: min: 6, max: 7000 (nM) from 6 assay(s)
IC50: min: 1.4, max: 245 (nM) from 6 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.83α = 90
b = 78.68β = 92.84
c = 99.96γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
d*TREKdata reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-15
    Type: Initial release
  • Version 1.1: 2013-05-22
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description