3NT1

High resolution structure of naproxen:COX-2 complex.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen.

Duggan, K.C.Walters, M.J.Musee, J.Harp, J.M.Kiefer, J.R.Oates, J.A.Marnett, L.J.

(2010) J Biol Chem 285: 34950-34959

  • DOI: https://doi.org/10.1074/jbc.M110.162982
  • Primary Citation of Related Structures:  
    3NT1, 3NTB

  • PubMed Abstract: 

    Naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions are tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH(2) for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 Å resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.


  • Organizational Affiliation

    AB Hancock Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute for Chemical Biology, the Center in Molecular Toxicology, Nashville, Tennessee 37232-0146.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Prostaglandin-endoperoxide synthase 2
A, B
587Mus musculusMutation(s): 0 
Gene Names: COX-2 PGHS-BmCG_5001Ptgs2
EC: 1.14.99.1
UniProt
Find proteins for Q05769 (Mus musculus)
Explore Q05769 
Go to UniProtKB:  Q05769
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05769
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C, D
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
I [auth A],
P [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
BOG
Query on BOG

Download Ideal Coordinates CCD File 
G [auth A],
J [auth A],
K [auth A],
O [auth B]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
NPS
Query on NPS

Download Ideal Coordinates CCD File 
H [auth A],
N [auth B]
(2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid
C14 H14 O3
CMWTZPSULFXXJA-VIFPVBQESA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
M [auth B],
Q [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
L [auth A],
R [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
NPS BindingDB:  3NT1 Ki: 1.00e+4 (nM) from 1 assay(s)
IC50: min: 60, max: 5.22e+4 (nM) from 10 assay(s)
Binding MOAD:  3NT1 IC50: 900 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 122.295α = 90
b = 133.233β = 90
c = 181.269γ = 90
Software Package:
Software NamePurpose
MAR345data collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-12-27
    Changes: Data collection, Database references, Structure summary