8R1B | pdb_00008r1b

Crystal structure of recombinant LasB from Pseudomonas aeruginosa PAO1 in complex with 6466

PDB DOI: https://doi.org/10.2210/pdb8R1B/pdb

Classification: HYDROLASE
Organism(s): Pseudomonas aeruginosa PAO1
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2023-11-01 Released: 2024-10-16
Deposition Author(s): Kolling, D., Koehnke, J.
Funding Organization(s): Other government

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.31 Å
R-Value Free:
0.167 (Depositor), 0.166 (DCC)
R-Value Work:
0.145 (Depositor), 0.144 (DCC)
R-Value Observed:
0.146 (Depositor)

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Dipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model.

Kiefer, A.F., Schutz, C., Englisch, C.N., Kolling, D., Speicher, S., Kany, A.M., Shafiei, R., Wadood, N.A., Aljohmani, A., Wirschem, N., Jumde, R.P., Klein, A., Sikandar, A., Park, Y.M., Krasteva-Christ, G., Yildiz, D., Abdelsamie, A.S., Rox, K., Kohnke, J., Muller, R., Bischoff, M., Haupenthal, J., Hirsch, A.K.H.

(2025) Adv Sci (Weinh) 12: e2411807-e2411807

PubMed: 39973061 Search on PubMed
DOI: https://doi.org/10.1002/advs.202411807
Primary Citation of Related Structures:
8R1B, 9FQD, 9FQY

PubMed Abstract:
The ubiquitous opportunistic pathogen Pseudomonas aeruginosa is responsible for severe infections and notoriously known for acquiring antimicrobial resistance. Inhibiting the bacterium's extracellular elastase, LasB - a zinc-dependent protease - presents a promising strategy to mitigate its virulence. Within this medicinal chemistry-driven hit-to-lead optimization campaign, a new series of highly potent dipeptidic phosphonates is designed and synthesized following a structure-based drug-discovery approach. In vitro and in vivo evaluation reveal beneficial pharmacokinetic profiles, excellent selectivity over human off-targets and good tolerability in murine toxicity studies. Ultimately, the scaffold presented herein demonstrates promising in vivo efficacy in a murine Pseudomonas aeruginosa keratitis model in combination with the antibiotic meropenem.

Organizational Affiliation

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123, Saarbrücken, Germany.

Macromolecule Content

Total Structure Weight: 56.53 kDa
Atom Count: 2,705
Modeled Residue Count: 298
Deposited Residue Count: 514
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Pro-elastase	A	514	Pseudomonas aeruginosa PAO1	Mutation(s): 0 Gene Names: lasB, PA3724 EC: 3.4.24.26
UniProt
Find proteins for P14756 (Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)) Explore P14756 Go to UniProtKB: P14756
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P14756
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
XI5 (Subject of Investigation/LOI) Query on XI5 Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A] mmCIF format, chain H [auth A]	H [auth A]	[(2~{S})-1-[[1-[(4-ethanoylphenyl)amino]-3-methyl-1-oxidanylidene-butan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]phosphonic acid C₁₉ H₂₉ N₂ O₆ P NDYKWZBIJQYUHB-IRXDYDNUSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	D [auth A], E [auth A], F [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain D [auth A] 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]
SCN Query on SCN 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]	THIOCYANATE ION C N S ZMZDMBWJUHKJPS-UHFFFAOYSA-M		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
CA Query on CA 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]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]