7NI3

CRYSTAL STRUCTURE OF NATIVE HUMAN MYELOPEROXIDASE IN COMPLEX WITH CPD 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.

Inghardt, T.Antonsson, T.Ericsson, C.Hovdal, D.Johannesson, P.Johansson, C.Jurva, U.Kajanus, J.Kull, B.Michaelsson, E.Pettersen, A.Sjogren, T.Sorensen, H.Westerlund, K.Lindstedt, E.L.

(2022) J Med Chem 65: 11485-11496

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c02141
  • Primary Citation of Related Structures:  
    7NI1, 7NI3

  • PubMed Abstract: 

    Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC 50 , 1.5 nM in vitro ) and selectivity (>450-fold vs thyroid peroxidase in vitro ), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2 b /3 efficacy study of AZD4831 in patients with HFpEF started in 2021.


  • Organizational Affiliation

    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 50 Mölndal, Gothenburg, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Myeloperoxidase
A, B
105Homo 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
C, D
466Homo 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
Glycosylation
Glycosylation Sites: 3Go to GlyGen: P05164-1
Sequence Annotations
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  • 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, F
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G32152BH
GlyCosmos:  G32152BH
GlyGen:  G32152BH
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
UE8 (Subject of Investigation/LOI)
Query on UE8

Download Ideal Coordinates CCD File 
M [auth C],
S [auth D]
2-sulfanylidene-3-[(2R)-tetrahydro-2-furanylmethyl]-1,2,3,7-tetrahydro-6H-purin-6-one
C10 H12 N4 O2 S
RSPDBEVKURKEII-ZCFIWIBFSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
P [auth C],
Q [auth C],
U [auth D],
V [auth D]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
BMA
Query on BMA

Download Ideal Coordinates CCD File 
R [auth C],
T [auth D]
beta-D-mannopyranose
C6 H12 O6
WQZGKKKJIJFFOK-RWOPYEJCSA-N
CA
Query on CA

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

Download Ideal Coordinates CCD File 
H [auth A],
I [auth B],
K [auth B],
L [auth C],
O [auth C]
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 92.66α = 90
b = 63.64β = 97.15
c = 111.03γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
STARANISOdata scaling
PHASERphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2022-02-23
    Type: Initial release
  • Version 1.1: 2022-04-20
    Changes: Database references
  • Version 1.2: 2022-08-31
    Changes: Database references
  • Version 1.3: 2022-09-07
    Changes: Database references
  • Version 1.4: 2022-09-21
    Changes: Database references
  • Version 1.5: 2024-01-31
    Changes: Data collection, Refinement description