4K5N

Phosphonic Arginine Mimetics as Inhibitors of the M1 Aminopeptidases from Plasmodium falciparum

PDB DOI: https://doi.org/10.2210/pdb4K5N/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Plasmodium falciparum FcB1/Columbia
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2013-04-15 Released: 2013-06-12
Deposition Author(s): McGowan, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.91 Å
R-Value Free: 0.210
R-Value Work: 0.161
R-Value Observed: 0.164

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

PubMed: 23713488 Search on PubMed
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.

Macromolecule Content

Total Structure Weight: 105.03 kDa
Atom Count: 8,291
Modelled Residue Count: 889
Deposited Residue Count: 895
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
M1 family aminopeptidase	A	895	Plasmodium falciparum FcB1/Columbia	Mutation(s): 7 EC: 3.4.11
UniProt
Find proteins for O96935 (Plasmodium falciparum (isolate 3D7)) Explore O96935 Go to UniProtKB: O96935
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O96935
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
1OU Query on 1OU Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	[(R)-amino(4-carbamimidamidophenyl)methyl]phosphonic acid C₈ H₁₃ N₄ O₃ P BSLYPYFABFFNHY-SSDOTTSWSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	E [auth A], F [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain H [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain H [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain H [auth A]	C [auth A], D [auth A], H [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain H [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain H [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
1OU	PDBBind: 4K5N	Ki: 1.27e+5 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.91 Å
R-Value Free: 0.210
R-Value Work: 0.161
R-Value Observed: 0.164
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 75.762	α = 90
b = 109.451	β = 90
c = 118.638	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
PDB_EXTRACT	data extraction
Blu-Ice	data collection
XDS	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

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