7OC0

Structure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid

PDB DOI: https://doi.org/10.2210/pdb7OC0/pdb

Classification: ANTIBIOTIC
Organism(s): Pseudomonas aeruginosa PAO1
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2021-04-25 Released: 2021-08-25
Deposition Author(s): Georgiou, C., Brenk, R., Espeland, L.O., Klein, R.
Funding Organization(s): Research Council of Norway

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.78 Å
R-Value Free: 0.188
R-Value Work: 0.154
R-Value Observed: 0.156

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

This is version 1.3 of the entry. See complete history.

Literature

An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.

Espeland, L.O., Georgiou, C., Klein, R., Bhukya, H., Haug, B.E., Underhaug, J., Mainkar, P.S., Brenk, R.

(2021) ChemMedChem 16: 2715-2726

PubMed: 34189850 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/cmdc.202100302
Primary Citation of Related Structures:
7OC0, 7OC1

PubMed Abstract:
FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.

Organizational Affiliation

Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5020, Bergen, Norway.

Macromolecule Content

Total Structure Weight: 87.57 kDa
Atom Count: 6,815
Modelled Residue Count: 823
Deposited Residue Count: 824
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
3-oxoacyl-[acyl-carrier-protein] synthase 2	A, B	412	Pseudomonas aeruginosa PAO1	Mutation(s): 1 Gene Names: fabF1, PA2965 EC: 2.3.1.179
UniProt
Find proteins for G3XDA2 (Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)) Explore G3XDA2 Go to UniProtKB: G3XDA2
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	G3XDA2
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
V7W (Subject of Investigation/LOI) Query on V7W Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain K [auth B] MOL2 format, chain C [auth A] MOL2 format, chain K [auth B] mmCIF format, chain C [auth A] mmCIF format, chain K [auth B]	C [auth A], K [auth B]	(2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid C₈ H₉ N O₂ S₂ ZUDFHYZUQCNUJF-FSPLSTOPSA-N		Interactions Focus chain C [auth A] Focus chain K [auth B] Interactions & Density Focus chain C [auth A] Focus chain K [auth B]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain H [auth B] SDF format, chain I [auth B] SDF format, chain J [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain H [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B]	D [auth A] E [auth A] G [auth B] H [auth B] I [auth B] D [auth A], E [auth A], G [auth B], H [auth B], I [auth B], J [auth B]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B]
MG Query on MG 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]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]