6SBR

The crystal structure of PfA-M1 in complex with 7-amino-1,4-dibromo-5,7,8,9-tetrahydrobenzocyclohepten-6-one

PDB DOI: https://doi.org/10.2210/pdb6SBR/pdb

Classification: HYDROLASE
Organism(s): Plasmodium falciparum 3D7
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2019-07-22 Released: 2020-03-25
Deposition Author(s): Salomon, E., Schmitt, M., Mouray, E., McEwen, A.G., Torchy, M., Poussin-Courmontagne, P., Alavi, S., Tarnus, C., Cavarelli, J., Florent, I., Albrecht, S.
Funding Organization(s): French National Research Agency

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.54 Å
R-Value Free: 0.181
R-Value Work: 0.143
R-Value Observed: 0.145

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 1.1 of the entry. See complete history.

Literature

Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.

Salomon, E., Schmitt, M., Mouray, E., McEwen, A.G., Bounaadja, L., Torchy, M., Poussin-Courmontagne, P., Alavi, S., Tarnus, C., Cavarelli, J., Florent, I., Albrecht, S.

(2020) Bioorg Chem 98: 103750-103750

PubMed: 32182520 Search on PubMed
DOI: https://doi.org/10.1016/j.bioorg.2020.103750
Primary Citation of Related Structures:
6SBQ, 6SBR

PubMed Abstract:
Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC ₅₀ values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.

Organizational Affiliation

Université de Haute-Alsace, Université de Strasbourg, CNRS, LIMA UMR 7042, F-68000 Mulhouse, France.

Macromolecule Content

Total Structure Weight: 108.45 kDa
Atom Count: 9,292
Modelled Residue Count: 891
Deposited Residue Count: 924
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
M1-family alanyl aminopeptidase	A	924	Plasmodium falciparum 3D7	Mutation(s): 0 Gene Names: PF3D7_1311800 EC: 3.4.11.2 (PDB Primary Data), 3.4.11 (UniProt)
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 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
L5E (Subject of Investigation/LOI) Query on L5E 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]	[(7~{S})-1,4-bis(bromanyl)-6,6-bis(oxidanyl)-5,7,8,9-tetrahydrobenzo[7]annulen-7-yl]azanium C₁₁ H₁₄ Br₂ N O₂ JKSZJUHJLDPZJQ-JTQLQIEISA-O		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
B3P Query on B3P Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL C₁₁ H₂₆ N₂ O₆ HHKZCCWKTZRCCL-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [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]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.54 Å
R-Value Free: 0.181
R-Value Work: 0.143
R-Value Observed: 0.145
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 77.161	α = 90
b = 109.662	β = 90
c = 113.519	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
Aimless	data scaling
PDB_EXTRACT	data extraction
PHENIX	phasing

Structure Validation

View Full Validation Report

Entry History & Funding Information

Deposition Data

Released Date: 2020-03-25

Deposition Author(s):

Poussin-Courmontagne, P.

Funding Organization	Location	Grant Number
French National Research Agency	France	ANR-12-BS07-0020-01
French National Research Agency	France	ANR-10-INBS-05
French National Research Agency	France	ANR-10-LABX-0030-INRT
French National Research Agency	France	ANR-10-IDEX-0002-02