4ZQT

Crystal structure of PfA-M1 with virtual ligand inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.

Ruggeri, C.Drinkwater, N.Sivaraman, K.K.Bamert, R.S.McGowan, S.Paiardini, A.

(2015) PLoS One 10: e0138957-e0138957

  • DOI: https://doi.org/10.1371/journal.pone.0138957
  • Primary Citation of Related Structures:  
    4ZQT, 5CBM

  • PubMed Abstract: 

    The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.


  • Organizational Affiliation

    Dipartimento di Scienze biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
M1 family aminopeptidase889Plasmodium falciparum 3D7Mutation(s): 7 
EC: 3.4.11
UniProt
Find proteins for O96935 (Plasmodium falciparum (isolate 3D7))
Explore O96935 
Go to UniProtKB:  O96935
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96935
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.35α = 90
b = 109.11β = 90
c = 118.05γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)Australia1063786
Australian Research Council (ARC)Australia100100690

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-07
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Author supporting evidence, Data collection, Derived calculations
  • Version 1.2: 2018-01-17
    Changes: Author supporting evidence
  • Version 1.3: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description