3PSY

Endothiapepsin in complex with an inhibitor based on the Gewald reaction


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.128 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.

Kuhnert, M.Koster, H.Bartholomaus, R.Park, A.Y.Shahim, A.Heine, A.Steuber, H.Klebe, G.Diederich, W.E.

(2015) Angew Chem Int Ed Engl 54: 2849-2853

  • DOI: https://doi.org/10.1002/anie.201411206
  • Primary Citation of Related Structures:  
    3PSY, 3WZ6, 3WZ7, 3WZ8

  • PubMed Abstract: 

    Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.


  • Organizational Affiliation

    Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 3, 35032 Marburg (Germany).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Endothiapepsin330Cryphonectria parasiticaMutation(s): 0 
EC: 3.4.23.22
UniProt
Find proteins for P11838 (Cryphonectria parasitica)
Explore P11838 
Go to UniProtKB:  P11838
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11838
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RB9
Query on RB9

Download Ideal Coordinates CCD File 
B [auth A]N-benzyl-2-({N-[2-(1H-indol-3-yl)ethyl]glycyl}amino)-4-phenylthiophene-3-carboxamide
C30 H28 N4 O2 S
NZMGUKNNKODUOD-UHFFFAOYSA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
F [auth A]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
E [auth A]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
C [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.128 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.45α = 90
b = 73.05β = 109.5
c = 52.78γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHASERphasing
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-12-07
    Type: Initial release
  • Version 1.1: 2019-12-11
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description