1KYN

Cathepsin-G


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.258 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design.

Greco, M.N.Hawkins, M.J.Powell, E.T.Almond Jr., H.R.Corcoran, T.W.de Garavilla, L.Kauffman, J.A.Recacha, R.Chattopadhyay, D.Andrade-Gordon, P.Maryanoff, B.E.

(2002) J Am Chem Soc 124: 3810-3811

  • DOI: https://doi.org/10.1021/ja017506h
  • Primary Citation of Related Structures:  
    1KYN

  • PubMed Abstract: 

    The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.


  • Organizational Affiliation

    Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cathepsin G
A, B
235Homo sapiensMutation(s): 0 
EC: 3.4.21.20
UniProt & NIH Common Fund Data Resources
Find proteins for P08311 (Homo sapiens)
Explore P08311 
Go to UniProtKB:  P08311
PHAROS:  P08311
GTEx:  ENSG00000100448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08311
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KTP
Query on KTP

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2-NAPHTHALEN-2-YL-1-NAPHTHALEN-1-YL-2-OXO-ETHYL)-PHOSPHONIC ACID
C22 H17 O4 P
OFHMUASCSJJNNA-JOCHJYFZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KTP BindingDB:  1KYN IC50: 4100 (nM) from 1 assay(s)
PDBBind:  1KYN IC50: 4100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.258 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.44α = 90
b = 59.44β = 90
c = 130.62γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
X-PLORrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2002-05-01
    Type: Initial release
  • Version 1.1: 2008-03-26
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance