6EZP

CATHEPSIN L IN COMPLEX WITH (3S,14E)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.37 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

Giroud, M.Dietzel, U.Anselm, L.Banner, D.Kuglstatter, A.Benz, J.Blanc, J.B.Gaufreteau, D.Liu, H.Lin, X.Stich, A.Kuhn, B.Schuler, F.Kaiser, M.Brun, R.Schirmeister, T.Kisker, C.Diederich, F.Haap, W.

(2018) J Med Chem 61: 3350-3369

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01869
  • Primary Citation of Related Structures:  
    6EX8, 6EXO, 6EXQ, 6EZP, 6EZX, 6F06

  • PubMed Abstract: 

    Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K i < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC 50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.


  • Organizational Affiliation

    Laboratorium für Organische Chemie , ETH Zurich , Vladimir-Prelog-Weg 3 , 8093 Zürich , Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin L1220Homo sapiensMutation(s): 0 
Gene Names: CTSLCTSL1
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
C3E (Subject of Investigation/LOI)
Query on C3E

Download Ideal Coordinates CCD File 
B [auth A](3~{S},14~{E})-19-chloranyl-~{N}-(1-cyanocyclopropyl)-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide
C24 H22 Cl N3 O4
DAGMBGOOMHAGIF-RTLBZRNLSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
C3E BindingDB:  6EZP IC50: 13.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.37 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.056α = 90
b = 60.547β = 90
c = 70.049γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XPREPdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-11
    Type: Initial release
  • Version 1.1: 2018-05-09
    Changes: Data collection, Database references