4K5Z

Crystal Structure of Human Chymase in Complex with Fragment Inhibitor 6-chloro-2,3-dihydro-1H-isoindol-1-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.

Taylor, S.J.Padyana, A.K.Abeywardane, A.Liang, S.Hao, M.H.De Lombaert, S.Proudfoot, J.Farmer, B.S.Li, X.Collins, B.Martin, L.Albaugh, D.R.Hill-Drzewi, M.Pullen, S.S.Takahashi, H.

(2013) J Med Chem 56: 4465-4481

  • DOI: https://doi.org/10.1021/jm400138z
  • Primary Citation of Related Structures:  
    4K2Y, 4K5Z, 4K60, 4K69

  • PubMed Abstract: 

    Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. steven.taylor@boehringeringelheim.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chymase226Homo sapiensMutation(s): 0 
Gene Names: CMA1CYHCYM
EC: 3.4.21.39
UniProt & NIH Common Fund Data Resources
Find proteins for P23946 (Homo sapiens)
Explore P23946 
Go to UniProtKB:  P23946
PHAROS:  P23946
GTEx:  ENSG00000092009 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23946
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
B [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
1P7
Query on 1P7

Download Ideal Coordinates CCD File 
D [auth A]6-chloro-2,3-dihydro-1H-isoindol-1-one
C8 H6 Cl N O
VCEOKEOSVQLRNW-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1P7 PDBBind:  4K5Z IC50: 1.00e+6 (nM) from 1 assay(s)
BindingDB:  4K5Z IC50: 1.00e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 
  • Space Group: P 43
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.609α = 90
b = 74.609β = 90
c = 49.897γ = 90
Software Package:
Software NamePurpose
d*TREKdata reduction
PHENIXrefinement
PDB_EXTRACTdata extraction
StructureStudiodata collection
d*TREKdata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-29
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations, Structure summary