5CBM

Crystal structure of PfA-M17 with virtual ligand inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


This is version 1.1 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
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
M17 family aminopeptidase
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L
519Plasmodium falciparum Vietnam Oak-Knoll (FVO)Mutation(s): 3 
Gene Names: PFFVO_05086
UniProt
Find proteins for A0A024V0B1 (Plasmodium falciparum Vietnam Oak-Knoll)
Explore A0A024V0B1 
Go to UniProtKB:  A0A024V0B1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A024V0B1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4ZN
Query on 4ZN
Download Ideal Coordinates CCD File 
AB [auth E]
BA [auth B]
BC [auth H]
GD [auth L]
HC [auth I]
AB [auth E],
BA [auth B],
BC [auth H],
GD [auth L],
HC [auth I],
IA [auth C],
JB [auth F],
P [auth A],
PC [auth J],
QB [auth G],
TA [auth D],
YC [auth K]
(2S)-2-{[(R)-[(R)-amino(phenyl)methyl](hydroxy)phosphoryl]methyl}-4-methylpentanoic acid
C14 H22 N O4 P
RUYPIGFYJMPICK-CHWSQXEVSA-N
1PE
Query on 1PE
Download Ideal Coordinates CCD File 
AD [auth K]
BB [auth E]
CA [auth B]
CB [auth E]
CC [auth H]
AD [auth K],
BB [auth E],
CA [auth B],
CB [auth E],
CC [auth H],
DA [auth B],
DC [auth H],
HD [auth L],
IC [auth I],
ID [auth L],
JA [auth C],
JC [auth I],
KA [auth C],
KB [auth F],
Q [auth A],
QC [auth J],
R [auth A],
RB [auth G],
RC [auth J],
SB [auth G],
SC [auth J],
TB [auth G],
UA [auth D],
VA [auth D],
ZC [auth K]
PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
BD [auth K]
CD [auth K]
DB [auth E]
EA [auth B]
EB [auth E]
BD [auth K],
CD [auth K],
DB [auth E],
EA [auth B],
EB [auth E],
FB [auth E],
JD [auth L],
KC [auth I],
LA [auth C],
LB [auth F],
LC [auth I],
MA [auth C],
MB [auth F],
NA [auth C],
OA [auth C],
PA [auth C],
T [auth A],
TC [auth J],
U [auth A],
UB [auth G],
UC [auth J],
V [auth A],
VB [auth G],
W [auth A],
WA [auth D],
WB [auth G],
X [auth A],
XB [auth G]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
S [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
AA [auth B]
AC [auth H]
ED [auth L]
FC [auth I]
FD [auth L]
AA [auth B],
AC [auth H],
ED [auth L],
FC [auth I],
FD [auth L],
GA [auth C],
GC [auth I],
HA [auth C],
HB [auth F],
IB [auth F],
N [auth A],
NC [auth J],
O [auth A],
OB [auth G],
OC [auth J],
PB [auth G],
RA [auth D],
SA [auth D],
WC [auth K],
XC [auth K],
YA [auth E],
Z [auth B],
ZA [auth E],
ZB [auth H]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CO3
Query on CO3
Download Ideal Coordinates CCD File 
DD [auth L]
EC [auth I]
FA [auth C]
GB [auth F]
M [auth A]
DD [auth L],
EC [auth I],
FA [auth C],
GB [auth F],
M [auth A],
MC [auth J],
NB [auth G],
QA [auth D],
VC [auth K],
XA [auth E],
Y [auth B],
YB [auth H]
CARBONATE ION
C O3
BVKZGUZCCUSVTD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 174.092α = 90
b = 177.728β = 90
c = 230.981γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-07
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description