1NPZ

Crystal structures of Cathepsin S inhibitor complexes


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Specificity determinants of human cathepsin s revealed by crystal structures of complexes.

Pauly, T.A.Sulea, T.Ammirati, M.Sivaraman, J.Danley, D.E.Griffor, M.C.Kamath, A.V.Wang, I.K.Laird, E.R.Seddon, A.P.Menard, R.Cygler, M.Rath, V.L.

(2003) Biochemistry 42: 3203-3213

  • DOI: https://doi.org/10.1021/bi027308i
  • Primary Citation of Related Structures:  
    1NPZ, 1NQC

  • PubMed Abstract: 

    Cathepsin S, a lysosomal cysteine protease of the papain superfamily, has been implicated in the preparation of MHC class II alphabeta-heterodimers for antigen presentation to CD4+ T lymphocytes and is considered a potential target for autoimmune-disease therapy. Selective inhibition of this enzyme may be therapeutically useful for attenuating the hyperimmune responses in a number of disorders. We determined the three-dimensional crystal structures of human cathepsin S in complex with potent covalent inhibitors, the aldehyde inhibitor 4-morpholinecarbonyl-Phe-(S-benzyl)Cys-Psi(CH=O), and the vinyl sulfone irreversible inhibitor 4-morpholinecarbonyl-Leu-Hph-Psi(CH=CH-SO(2)-phenyl) at resolutions of 1.8 and 2.0 A, respectively. In the structure of the cathepsin S-aldehyde complex, the tetrahedral thiohemiacetal adduct favors the S-configuration, in which the oxygen atom interacts with the imidazole group of the active site His164 rather than with the oxyanion hole. The present structures provide a detailed map of noncovalent intermolecular interactions established in the substrate-binding subsites S3 to S1' of cathepsin S. In the S2 pocket, which is the binding affinity hot spot of cathepsin S, the Phe211 side chain can assume two stable conformations that accommodate either the P2-Leu or a bulkier P2-Phe side chain. This structural plasticity of the S2 pocket in cathepsin S explains the selective inhibition of cathepsin S over cathepsin K afforded by inhibitors with the P2-Phe side chain. Comparison with the structures of cathepsins K, V, and L allows delineation of local intermolecular contacts that are unique to cathepsin S.


  • Organizational Affiliation

    Exploratory Medicinal Sciences and Computational Chemistry, Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin S
A, B
217Homo sapiensMutation(s): 0 
EC: 3.4.22.27
UniProt & NIH Common Fund Data Resources
Find proteins for P25774 (Homo sapiens)
Explore P25774 
Go to UniProtKB:  P25774
PHAROS:  P25774
GTEx:  ENSG00000163131 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25774
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C1P
Query on C1P

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N~2~-(morpholin-4-ylcarbonyl)-N-[(3S)-1-phenyl-5-(phenylsulfonyl)pentan-3-yl]-L-leucinamide
C28 H39 N3 O5 S
IHIAYQGDASIWGA-AHWVRZQESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
C1P PDBBind:  1NPZ Ki: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.192 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 108.083α = 90
b = 108.083β = 90
c = 105.305γ = 120
Software Package:
Software NamePurpose
MAR345data collection
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-15
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2011-09-07
    Changes: Non-polymer description
  • Version 1.4: 2017-10-11
    Changes: Refinement description
  • Version 1.5: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description