4PH9

The structure of Ibuprofen bound to cyclooxygenase-2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 

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Ligand Structure Quality Assessment 


This is version 3.1 of the entry. See complete history


Literature

The structure of ibuprofen bound to cyclooxygenase-2.

Orlando, B.J.Lucido, M.J.Malkowski, M.G.

(2015) J Struct Biol 189: 62-66

  • DOI: https://doi.org/10.1016/j.jsb.2014.11.005
  • Primary Citation of Related Structures:  
    4PH9

  • PubMed Abstract: 

    The cyclooxygenases (COX-1 and COX-2) catalyze the rate-limiting step in the biosynthesis of prostaglandins, and are the pharmacological targets of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors (coxibs). Ibuprofen (IBP) is one of the most commonly available over-the-counter pharmaceuticals in the world. The anti-inflammatory and analgesic properties of IBP are thought to arise from inhibition of COX-2 rather than COX-1. While an X-ray crystal structure of IBP bound to COX-1 has been solved, no such structure exists for the cognate isoform COX-2. We have determined the crystal structure of muCOX-2 with a racemic mixture of (R/S)-IBP. Our structure reveals that only the S-isomer of IBP was bound, indicating that the S-isomer possesses higher affinity for COX-2 than the R-isomer. Mutational analysis of Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel confirmed their role in binding and inhibition of COX-2 by IBP. Our results provide the first atomic level detail of the interaction between IBP and COX-2.


  • Organizational Affiliation

    Department of Structural Biology, The State University of New York at Buffalo and the Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Prostaglandin G/H synthase 2
A, B
551Mus musculusMutation(s): 0 
Gene Names: Ptgs2Cox-2Cox2Pghs-bTis10
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
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G62182OO
GlyCosmos:  G62182OO
GlyGen:  G62182OO
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

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

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A],
V [auth B]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
W [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
IBP
Query on IBP

Download Ideal Coordinates CCD File 
F [auth A],
T [auth B]
IBUPROFEN
C13 H18 O2
HEFNNWSXXWATRW-JTQLQIEISA-N
AKR
Query on AKR

Download Ideal Coordinates CCD File 
L [auth A],
M [auth A],
X [auth B],
Y [auth B]
ACRYLIC ACID
C3 H4 O2
NIXOWILDQLNWCW-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
CA [auth B]
DA [auth B]
EA [auth B]
AA [auth B],
BA [auth B],
CA [auth B],
DA [auth B],
EA [auth B],
FA [auth B],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
IBP BindingDB:  4PH9 Ki: min: 7200, max: 1.00e+4 (nM) from 4 assay(s)
IC50: min: 100, max: 3.70e+5 (nM) from 28 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.941α = 90
b = 132.228β = 90
c = 180.462γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data collection
HKL-2000data reduction
PHASERphasing
PDB_EXTRACTdata extraction
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01 GM077176

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-26
    Type: Initial release
  • Version 1.1: 2014-12-17
    Changes: Database references
  • Version 1.2: 2015-01-07
    Changes: Database references
  • Version 1.3: 2015-02-25
    Changes: Derived calculations
  • Version 2.0: 2017-09-06
    Changes: Atomic model, Author supporting evidence, Database references, Derived calculations, Other, Source and taxonomy, Structure summary
  • Version 2.1: 2017-11-22
    Changes: Refinement description
  • Version 2.2: 2019-12-25
    Changes: Author supporting evidence
  • Version 3.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Refinement description, Structure summary
  • Version 3.1: 2023-09-27
    Changes: Data collection, Database references, Refinement description, Structure summary