4X2T

X-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M17 Leucyl Aminopeptidase from P. falciparum

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.73 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 

Starting Model: experimental
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This is version 1.5 of the entry. See complete history. 


Literature

X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17.

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

(2015) Proteins 83: 789-795

  • DOI: https://doi.org/10.1002/prot.24771
  • Primary Citation of Related Structures:  
    4X2T, 4X2U

  • PubMed Abstract: 

    New anti-malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, PfA-M1 and PfA-M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes' putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17.

    • Organizational Affiliation: 

    Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, 3800, Australia.


Macromolecules
Find similar proteins by: 
(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
519Plasmodium 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
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TOD
Query on TOD
Download Ideal Coordinates CCD File 
AB [auth G]
AC [auth L]
CA [auth C]
IB [auth H]
NB [auth I]
AB [auth G],
AC [auth L],
CA [auth C],
IB [auth H],
NB [auth I],
O [auth A],
PA [auth E],
SB [auth J],
WA [auth F],
WB [auth K],
X [auth B]
(2S)-({(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}amino)(phenyl)ethanoic acid
C16 H22 N2 O6
FIVIXKOBUJPPEI-AGIUHOORSA-N
1PE
Query on 1PE
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EB [auth G]
FA [auth C]
FB [auth G]
GA [auth C]
KB [auth H]
EB [auth G],
FA [auth C],
FB [auth G],
GA [auth C],
KB [auth H],
LA [auth D],
MA [auth D],
T [auth A],
TA [auth E],
Z [auth B]
PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
SO4
Query on SO4
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CB [auth G]
CC [auth L]
DB [auth G]
DC [auth L]
EA [auth C]
CB [auth G],
CC [auth L],
DB [auth G],
DC [auth L],
EA [auth C],
KA [auth D],
PB [auth I],
Q [auth A],
R [auth A],
RA [auth E],
S [auth A],
SA [auth E],
Y [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN
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AA [auth C]
BA [auth C]
GB [auth H]
HA [auth D]
HB [auth H]
AA [auth C],
BA [auth C],
GB [auth H],
HA [auth D],
HB [auth H],
IA [auth D],
LB [auth I],
M [auth A],
MB [auth I],
N [auth A],
NA [auth E],
OA [auth E],
QB [auth J],
RB [auth J],
UA [auth F],
UB [auth K],
V [auth B],
VA [auth F],
VB [auth K],
W [auth B],
YA [auth G],
YB [auth L],
ZA [auth G],
ZB [auth L]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CO3
Query on CO3
Download Ideal Coordinates CCD File 
BB [auth G]
BC [auth L]
DA [auth C]
JA [auth D]
JB [auth H]
BB [auth G],
BC [auth L],
DA [auth C],
JA [auth D],
JB [auth H],
OB [auth I],
P [auth A],
QA [auth E],
TB [auth J],
U [auth B],
XA [auth F],
XB [auth K]
CARBONATE ION
C O3
BVKZGUZCCUSVTD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.73 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 173.715α = 90
b = 176.698β = 90
c = 223.977γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)Australia1063786
Australian Research Council (ARC)AustraliaFT100100690

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-18
    Type: Initial release
  • Version 1.1: 2015-04-08
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy
  • 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
  • Version 1.5: 2024-10-30
    Changes: Structure summary