3CUK

Crystal structure of human D-amino acid oxidase: bound to an inhibitor

PDB DOI: https://doi.org/10.2210/pdb3CUK/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2008-04-16 Released: 2008-07-22
Deposition Author(s): Prasad, S., Munshi, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.49 Å
R-Value Free: 0.329
R-Value Work: 0.239
R-Value Observed: 0.243

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.

Sparey, T., Abeywickrema, P., Almond, S., Brandon, N., Byrne, N., Campbell, A., Hutson, P.H., Jacobson, M., Jones, B., Munshi, S., Pascarella, D., Pike, A., Prasad, G.S., Sachs, N., Sakatis, M., Sardana, V., Venkatraman, S., Young, M.B.

(2008) Bioorg Med Chem Lett 18: 3386-3391

PubMed: 18455394 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2008.04.020
Primary Citation of Related Structures:
3CUK

PubMed Abstract:
The 'NMDA hypofunction hypothesis of schizophrenia' can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARs of 1.

Organizational Affiliation

Department of Medicinal Chemistry, Merck Sharp & Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. [email protected]

Macromolecule Content

Total Structure Weight: 161.83 kDa
Atom Count: 10,850
Modelled Residue Count: 1,308
Deposited Residue Count: 1,388
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
D-amino-acid oxidase	A, B, C, D	347	Homo sapiens	Mutation(s): 0 Gene Names: DAO, DAMOX 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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P14920
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FAD Query on FAD Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain I [auth C] mmCIF format, chain K [auth D]	E [auth A], G [auth B], I [auth C], K [auth D]	FLAVIN-ADENINE DINUCLEOTIDE C₂₇ H₃₃ N₉ O₁₅ P₂ VWWQXMAJTJZDQX-UYBVJOGSSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]
4P5 Query on 4P5 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain J [auth C] mmCIF format, chain L [auth D]	F [auth A], H [auth B], J [auth C], L [auth D]	4H-furo[3,2-b]pyrrole-5-carboxylic acid C₇ H₅ N O₃ MMAIBGHDBYQYDI-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D]

Binding Affinity Annotations
ID	Source	Binding Affinity
4P5	BindingDB: 3CUK	Ki: 36 (nM) from 1 assay(s)
		Kd: min: 3.1, max: 37 (nM) from 4 assay(s)
		IC50: min: 9, max: 214 (nM) from 5 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.49 Å
R-Value Free: 0.329
R-Value Work: 0.239
R-Value Observed: 0.243
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 187.729	α = 90
b = 51.145	β = 110.45
c = 153.294	γ = 90

Software Package:

Software Name	Purpose
MOLREP	phasing
REFMAC	refinement
HKL-2000	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2008-07-22

Deposition Author(s):

Prasad, S.

Munshi, S.

Revision History (Full details and data files)

Version 1.0: 2008-07-22
Type: Initial release
Version 1.1: 2011-07-13
Changes: Advisory, Version format compliance
Version 1.2: 2018-03-14
Changes: Data collection
Version 1.3: 2023-08-30
Changes: Data collection, Database references, Derived calculations, Refinement description