4CKU

Three dimensional structure of plasmepsin II in complex with hydroxyethylamine-based inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit.

Jaudzems, K., Tars, K., Maurops, G., Ivdra, N., Otikovs, M., Leitans, J., Kanepe-Lapsa, I., Domraceva, I., Mutule, I., Trapencieris, P., Blackman, M.J., Jirgensons, A.

(2014) ACS Med Chem Lett 5: 373

  • DOI: https://doi.org/10.1021/ml4004952
  • Primary Citation of Related Structures:  
    4CKU

  • PubMed Abstract: 

    Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

    • Organizational Affiliation: 

    Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PLASMEPSIN-2
A, B, C, D, E
A, B, C, D, E, F
329Plasmodium falciparumMutation(s): 0 
EC: 3.4.23.39
UniProt
Find proteins for P46925 (Plasmodium falciparum (isolate HB3))
Explore P46925 
Go to UniProtKB:  P46925
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP46925
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
P2F Binding MOAD:  4CKU IC50: 150 (nM) from 1 assay(s)
BindingDB:  4CKU IC50: 150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 201.95α = 90
b = 115.25β = 110.75
c = 93.17γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-18
    Type: Initial release
  • Version 1.1: 2018-01-17
    Changes: Data collection
  • Version 1.2: 2019-01-30
    Changes: Data collection, Experimental preparation
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description