3ZS1

Human Myeloperoxidase inactivated by TX5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

2-Thioxanthines are Mechanism-Based Inactivators of Myeloperoxidase that Block Oxidative Stress During Inflammation.

Tiden, A.K.Sjogren, T.Svensson, M.Bernlind, A.Senthilmohan, R.Auchere, F.Norman, H.Markgren, P.O.Gustavsson, S.Schmidt, S.Lundquist, S.Forbes, L.V.Magon, N.J.Paton, L.N.Jameson, G.N.Eriksson, H.Kettle, A.J.

(2011) J Biol Chem 286: 37578

  • DOI: https://doi.org/10.1074/jbc.M111.266981
  • Primary Citation of Related Structures:  
    3ZS0, 3ZS1

  • PubMed Abstract: 

    Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation.


  • Organizational Affiliation

    AstraZeneca R&D, Södertälje SE-151 85, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MYELOPEROXIDASE LIGHT CHAIN
A, B
114Homo sapiensMutation(s): 0 
EC: 1.11.2.2
UniProt & NIH Common Fund Data Resources
Find proteins for P05164 (Homo sapiens)
Explore P05164 
Go to UniProtKB:  P05164
PHAROS:  P05164
GTEx:  ENSG00000005381 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05164
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
MYELOPEROXIDASE HEAVY CHAIN
C, D
467Homo sapiensMutation(s): 0 
EC: 1.11.2.2
UniProt & NIH Common Fund Data Resources
Find proteins for P05164 (Homo sapiens)
Explore P05164 
Go to UniProtKB:  P05164
PHAROS:  P05164
GTEx:  ENSG00000005381 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05164
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
E
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G32152BH
GlyCosmos:  G32152BH
GlyGen:  G32152BH
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G15407YE
GlyCosmos:  G15407YE
GlyGen:  G15407YE
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

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

Download Ideal Coordinates CCD File 
H [auth A],
J [auth B]
3-(2-METHOXYETHYL)-2-THIOXO-1,2,3,7-TETRAHYDRO-6H-PURIN-6-ONE
C8 H10 N4 O2 S
VXTADZREIUKIHH-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
AA [auth D],
R [auth C],
S [auth C],
Z [auth D]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
K [auth C],
N [auth C],
T [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ACT
Query on ACT

Download Ideal Coordinates CCD File 
O [auth C]
P [auth C]
Q [auth C]
W [auth D]
X [auth D]
O [auth C],
P [auth C],
Q [auth C],
W [auth D],
X [auth D],
Y [auth D]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CA
Query on CA

Download Ideal Coordinates CCD File 
L [auth C],
U [auth D]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
M [auth C],
V [auth D]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
C, D
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
PVW BindingDB:  3ZS1 IC50: 400 (nM) from 1 assay(s)
PDBBind:  3ZS1 IC50: 400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.13α = 90
b = 63.79β = 97.32
c = 111.35γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-31
    Type: Initial release
  • Version 1.1: 2012-08-15
    Changes: Database references
  • Version 1.2: 2015-09-16
    Changes: Source and taxonomy
  • Version 1.3: 2017-06-28
    Changes: Data collection
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 2.1: 2023-12-20
    Changes: Data collection, Database references, Refinement description, Structure summary