4K3N

Phosphonic Arginine Mimetics as Inhibitors of the M17 Aminopeptidases from Plasmodium falciparum

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Synthesis and Structure-Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum.

Kannan Sivaraman, K., Paiardini, A., Sienczyk, M., Ruggeri, C., Oellig, C.A., Dalton, J.P., Scammells, P.J., Drag, M., McGowan, S.

(2013) J Med Chem 56: 5213-5217

  • DOI: https://doi.org/10.1021/jm4005972
  • Primary Citation of Related Structures:  
    4K3N, 4K5L, 4K5M, 4K5N, 4K5O, 4K5P

  • PubMed Abstract: 

    The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.

    • Organizational Affiliation: 

    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
M17 leucyl aminopeptidase
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L
528Plasmodium falciparum 3D7Mutation(s): 3 
Gene Names: LAP, PF14_0439
EC: 3.4.13 (UniProt), 3.4.11.1 (UniProt)
UniProt
Find proteins for Q8IL11 (Plasmodium falciparum (isolate 3D7))
Explore Q8IL11 
Go to UniProtKB:  Q8IL11
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8IL11
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2PE
Query on 2PE
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BA [auth B]
CA [auth B]
DD [auth J]
HB [auth E]
IC [auth H]
BA [auth B],
CA [auth B],
DD [auth J],
HB [auth E],
IC [auth H],
JC [auth H],
LA [auth C],
RB [auth F],
TC [auth I],
VA [auth D],
WA [auth D],
XA [auth D]
NONAETHYLENE GLYCOL
C18 H38 O10
YZUUTMGDONTGTN-UHFFFAOYSA-N
1OT
Query on 1OT
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BB [auth E]
GA [auth C]
GC [auth H]
HD [auth K]
LB [auth F]
BB [auth E],
GA [auth C],
GC [auth H],
HD [auth K],
LB [auth F],
NC [auth I],
P [auth A],
PA [auth D],
RD [auth L],
VB [auth G],
XC [auth J],
Z [auth B]
{(R)-amino[4-(1H-pyrazol-1-yl)phenyl]methyl}phosphonic acid
C10 H12 N3 O3 P
KEKSMECJAGVZSC-SNVBAGLBSA-N
1PE
Query on 1PE
Download Ideal Coordinates CCD File 
AC [auth G]
AD [auth J]
BC [auth G]
BD [auth J]
CC [auth G]
AC [auth G],
AD [auth J],
BC [auth G],
BD [auth J],
CC [auth G],
CD [auth J],
EB [auth E],
FB [auth E],
GB [auth E],
IA [auth C],
JA [auth C],
KA [auth C],
KD [auth K],
LD [auth K],
MD [auth K],
NB [auth F],
ND [auth K],
OB [auth F],
PB [auth F],
QB [auth F],
QC [auth I],
RC [auth I],
SA [auth D],
SC [auth I],
TA [auth D],
TD [auth L],
U [auth A],
UA [auth D],
UD [auth L],
V [auth A],
VD [auth L],
WD [auth L],
ZB [auth G],
ZC [auth J]
PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
SO4
Query on SO4
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AA [auth B]
CB [auth E]
DB [auth E]
HA [auth C]
HC [auth H]
AA [auth B],
CB [auth E],
DB [auth E],
HA [auth C],
HC [auth H],
ID [auth K],
JD [auth K],
MB [auth F],
OC [auth I],
PC [auth I],
Q [auth A],
QA [auth D],
R [auth A],
RA [auth D],
S [auth A],
SD [auth L],
T [auth A],
WB [auth G],
XB [auth G],
YB [auth G],
YC [auth J]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN
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AB [auth E]
DA [auth C]
DC [auth H]
ED [auth K]
FA [auth C]
AB [auth E],
DA [auth C],
DC [auth H],
ED [auth K],
FA [auth C],
FC [auth H],
GD [auth K],
IB [auth F],
KB [auth F],
KC [auth I],
M [auth A],
MA [auth D],
MC [auth I],
O [auth A],
OA [auth D],
OD [auth L],
QD [auth L],
SB [auth G],
UB [auth G],
UC [auth J],
W [auth B],
WC [auth J],
Y [auth B],
YA [auth E]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CO3
Query on CO3
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EA [auth C]
EC [auth H]
FD [auth K]
JB [auth F]
LC [auth I]
EA [auth C],
EC [auth H],
FD [auth K],
JB [auth F],
LC [auth I],
N [auth A],
NA [auth D],
PD [auth L],
TB [auth G],
VC [auth J],
X [auth B],
ZA [auth E]
CARBONATE ION
C O3
BVKZGUZCCUSVTD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
1OT PDBBind:  4K3N Ki: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 173.716α = 90
b = 177.079β = 90
c = 229.185γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2013-06-12 
    • Deposition Author(s): McGowan, S.

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-12
    Type: Initial release
  • Version 1.1: 2013-07-24
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description