6EA1

X-ray crystal structure of Pf-M1 in complex with inhibitor (6da) and catalytic zinc ion


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.

Vinh, N.B.Drinkwater, N.Malcolm, T.R.Kassiou, M.Lucantoni, L.Grin, P.M.Butler, G.S.Duffy, S.Overall, C.M.Avery, V.M.Scammells, P.J.McGowan, S.

(2019) J Med Chem 62: 622-640

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01310
  • Primary Citation of Related Structures:  
    6EA1, 6EA2, 6EAA, 6EAB, 6EE2, 6EE3, 6EE4, 6EE6, 6EED, 6EEE

  • PubMed Abstract: 

    There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.


  • Organizational Affiliation

    Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences , Monash University, Parkville , Melbourne , VIC 3052 , Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
M1 family aminopeptidase889Plasmodium falciparum FcB1/ColumbiaMutation(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
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
J0Y (Subject of Investigation/LOI)
Query on J0Y

Download Ideal Coordinates CCD File 
C [auth A](2R)-2,3,3,3-tetrafluoro-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro[1,1'-biphenyl]-4-yl)ethyl]propanamide
C17 H11 F7 N2 O3
RMDXUADAMJFUFR-ZIAGYGMSSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
K [auth A],
L [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.491α = 90
b = 108.92β = 90
c = 118.15γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

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)AustraliaFT100100690

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-26
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references, Derived calculations