Binding properties of pyochelin and structurally related molecules to FptA of Pseudomonas aeruginosa

Autor: Isabelle J. Schalk, Keith Poole, Gaëtan L.A. Mislin, Françoise Hoegy, Didier Rognan, David Cobessi
Přispěvatelé: Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Klotz, Evelyne
Jazyk: angličtina
Rok vydání: 2006
Předmět:
Models
Molecular
Siderophore
Denticity
Protein Conformation
Siderophores
Crystallography
X-Ray
Ligands
MESH: Phenols
MESH: Protein Conformation
Structural Biology
Models
Receptors
MESH: Ligands
Non-U.S. Gov't
MESH: Receptors
Cell Surface
0303 health sciences
MESH: Iron
Crystallography
biology
Molecular Structure
Chemistry
Iron/chemistry/metabolism
Pseudomonas aeruginosa/*metabolism
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biomolecules [q-bio.BM]
Cell Surface
MESH: Pseudomonas aeruginosa
Pseudomonas aeruginosa
Bacterial outer membrane
MESH: Models
Molecular
Bacterial Outer Membrane Proteins
Stereochemistry
Iron
MESH: Molecular Structure
MESH: Thiazoles
Receptors
Cell Surface
Research Support
03 medical and health sciences
Phenols
Bacterial Outer Membrane Proteins/chemistry/metabolism
Phenols/chemistry/metabolism
Molecule
Chelation
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
MESH: Siderophores
Molecular Biology
030304 developmental biology
Siderophores/chemistry/metabolism
030306 microbiology
MESH: Bacterial Outer Membrane Proteins
Diastereomer
Molecular
biology.organism_classification
MESH: Crystallography
X-Ray
Thiazoles
Burkholderia
Docking (molecular)
Cell Surface/chemistry/metabolism
X-Ray
Thiazoles/chemistry/metabolism
Zdroj: Journal of Molecular Biology
Journal of Molecular Biology, Elsevier, 2006, 357, pp.1437-48
Journal of Molecular Biology, Elsevier, 2006, 357 (5), pp.1437-48. ⟨10.1016/j.jmb.2006.01.080⟩
ISSN: 0022-2836
1089-8638
DOI: 10.1016/j.jmb.2006.01.080⟩
Popis: 0022-2836 (Print) Journal Article; Pyochelin (Pch) is a siderophore that is produced in iron-limited conditions, by both Pseudomonas aeruginosa and Burkholderia cepacia. This iron uptake pathway could therefore be a target for the development of new antibiotics. Pch is (4'R,2''R/S,4''R)-2'-(2-hydroxyphenyl)-3''-methyl-4',5',2'',3'',4'',5''-he xahydro-[4',2'']bithiazolyl-4''-carboxylic acid, and has three chiral centres located at positions C4', C2'' and C4''. In P.aeruginosa, this siderophore chelates iron in the extracellular medium and transports it into the cells via a specific outer membrane transporter FptA. Docking experiments using the X-ray structure of FptA-Pch-Fe showed that iron-loaded or unloaded Pch diastereoisomers could bind to FptA. This was confirmed by in vivo binding assays. These binding properties and the iron uptake ability were not affected by removal of the C4' chiral centre. After removal of both the C4' and C2'' chiral centres, the molecule still bound to FptA but was unable to transport iron. The overall binding mode of this iron-complexed analogue was inverted. These findings describe the first antagonist of the Pch/FptA iron uptake pathway. Pch also complexes with iron in conjunction with other bidentate ligands such as cepabactin (Cep) or ethylene glycol. Docking experiments showed that such complexes bind to FptA via the Pch molecule. The mixed Pch-Fe-Cep complex was also recognized by FptA, having an affinity intermediate between that for Pch(2)-Fe and Cep(3)-Fe. Finally, the iron uptake properties of the different Pch-related molecules suggested a mechanism for FptA-Pch-Fe complex formation similar to that of the FpvA/Pvd uptake system. All these findings improve our understanding of specificity of the interaction between FptA and its siderophore.
Databáze: OpenAIRE
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