3PLD

Endothiapepsin in complex with a fragment


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.129 

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This is version 1.2 of the entry. See complete history


Literature

A small nonrule of 3 compatible fragment library provides high hit rate of endothiapepsin crystal structures with various fragment chemotypes.

Koster, H.Craan, T.Brass, S.Herhaus, C.Zentgraf, M.Neumann, L.Heine, A.Klebe, G.

(2011) J Med Chem 54: 7784-7796

  • DOI: https://doi.org/10.1021/jm200642w
  • Primary Citation of Related Structures:  
    3PB5, 3PBD, 3PBZ, 3PCW, 3PGI, 3PI0, 3PLD, 3PLL, 3PM4, 3PMU, 3PMY

  • PubMed Abstract: 

    Druglike molecules are defined by Lipinski's rule of 5, to characterize fragment thresholds, they have been reduced from 5 to 3 (Astex's rule of 3). They are applied to assemble fragment libraries, and providers use them to select fragments for commercial offer. We question whether these rules are too stringent to compose fragment libraries with candidates exhibiting sufficient room for chemical subsequent growing and merging modifications as appropriate functional groups for chemical transformations are required. Usually these groups exhibit properties as hydrogen bond donors/acceptors and provide entry points for optimization chemistry. We therefore designed a fragment library (364 entries) without strictly applying the rule of 3. For initial screening for endothiapepsin binding, we performed a biochemical cleavage assay of a fluorogenic substrate at 1 mM. "Hits" were defined to inhibit the enzyme by at least 40%. Fifty-five hits were suggested and subsequently soaked into endothiapepsin crystals. Eleven crystal structures could be determined covering fragments with diverse binding modes: (i) direct binding to the catalytic dyad aspartates, (ii) water-mediated binding to the aspartates, (iii) no direct interaction with the dyad. They occupy different specificity pockets. Only 4 of the 11 fragments are consistent with the rule of 3. Restriction to this rule would have limited the fragment hits to a strongly reduced variety of chemotypes.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
F90
Query on F90

Download Ideal Coordinates CCD File 
B [auth A]4-chlorobenzyl carbamimidothioate
C8 H9 Cl N2 S
YOCWIHYZDHPSHD-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.129 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.31α = 90
b = 73.01β = 109.64
c = 52.82γ = 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: 2011-11-02
    Type: Initial release
  • Version 1.1: 2011-11-30
    Changes: Database references
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description