4X2U

X-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M1 Alanyl Aminopeptidase from P. falciparum

PDB DOI: https://doi.org/10.2210/pdb4X2U/pdb

Classification: Hydrolase/Hydrolase Inhibitor
Organism(s): Plasmodium falciparum FcB1/Columbia
Expression System: Escherichia coli BL21
Mutation(s): Yes

Deposited: 2014-11-27 Released: 2015-02-18
Deposition Author(s): Drinkwater, N., McGowan, S.
Funding Organization(s): National Health and Medical Research Council (NHMRC, Australia), Australian Research Council (ARC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.50 Å
R-Value Free: 0.188
R-Value Work: 0.157
R-Value Observed: 0.158

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 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

PubMed: 25645579 Search on PubMed
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.

Macromolecule Content

Total Structure Weight: 104.87 kDa
Atom Count: 8,664
Modelled Residue Count: 889
Deposited Residue Count: 889
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	889	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
TOD Query on TOD Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	(2S)-({(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}amino)(phenyl)ethanoic acid C₁₆ H₂₂ N₂ O₆ FIVIXKOBUJPPEI-AGIUHOORSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A]	F [auth A] G [auth A] H [auth A] I [auth A] J [auth A] F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [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 D [auth A] SDF format, chain E [auth A] SDF format, chain N [auth A] SDF format, chain O [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain N [auth A] mmCIF format, chain O [auth A]	D [auth A], E [auth A], N [auth A], O [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain N [auth A] Focus chain O [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain N [auth A] Focus chain O [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.50 Å
R-Value Free: 0.188
R-Value Work: 0.157
R-Value Observed: 0.158
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 75.472	α = 90
b = 108.675	β = 90
c = 118.428	γ = 90

Software Package:

Software Name	Purpose
Aimless	data scaling
PHENIX	refinement
PDB_EXTRACT	data extraction
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2015-02-18

Deposition Author(s):

Drinkwater, N.

McGowan, S.

Funding Organization	Location	Grant Number
National Health and Medical Research Council (NHMRC, Australia)	Australia	1063786
Australian Research Council (ARC)	Australia	FT100100690

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