2YJ8

CATHEPSIN L WITH A NITRILE INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.143 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Halogen Bonding at the Active Sites of Human Cathepsin L and Mek1 Kinase: Efficient Interactions in Different Environments.

Hardegger, L.A.Kuhn, B.Spinnler, B.Anselm, L.Ecabert, R.Stihle, M.Gsell, B.Thoma, R.Diez, J.Benz, J.M.Plancher, J.Hartmann, G.Isshiki, Y.Morikami, K.Shimma, N.Haap, W.Banner, D.W.Diederich, F.

(2011) ChemMedChem 6: 2048

  • DOI: https://doi.org/10.1002/cmdc.201100353
  • Primary Citation of Related Structures:  
    2YJ2, 2YJ8, 2YJ9, 2YJB, 2YJC

  • PubMed Abstract: 

    In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.


  • Organizational Affiliation

    Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, HCI, 8093 Zürich, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CATHEPSIN L1220Homo sapiensMutation(s): 0 
EC: 3.4.22.15
UniProt & NIH Common Fund Data Resources
Find proteins for P07711 (Homo sapiens)
Explore P07711 
Go to UniProtKB:  P07711
PHAROS:  P07711
GTEx:  ENSG00000135047 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07711
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YJ8
Query on YJ8

Download Ideal Coordinates CCD File 
B [auth A](2S,4R)-4-(2-chlorophenyl)sulfonyl-N-[1-(iminomethyl)cyclopropyl]-1-[1-(4-iodophenyl)cyclopropyl]carbonyl-pyrrolidine-2-carboxamide
C25 H25 Cl I N3 O4 S
UYNFQDPYPNDGRC-OIRADOGLSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YJ8 PDBBind:  2YJ8 IC50: 6.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.143 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.975α = 90
b = 57.265β = 90
c = 76.218γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SADABSdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-23
    Type: Initial release