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Structural basis for the binding of naproxen to human serum albumin in the presence of fatty acids and the GA module
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2008 (English)In: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, ISSN 1744-3091, E-ISSN 1744-3091, Vol. 64, no Pt 2, 64-69 p.Article in journal (Refereed) Published
Abstract [en]

The previously determined crystal structure of the bacterial albumin-binding GA module in complex with human serum albumin (HSA) suggested the possibility of utilizing the complex in the study of ligand binding to HSA. As a continuation of these studies, the crystal structure of the HSA-GA complex with the drug molecule naproxen and the fatty acid decanoate bound to HSA has been determined to a resolution of 2.5 A. In terms of drug binding, the structure suggests that the binding of decanoate to the albumin molecule may play a role in making the haemin site in subdomain IB of the albumin molecule available for the binding of naproxen. In addition, structure comparisons with solved structures of HSA and of the HSA-GA complex show that the GA module is capable of binding to different conformations of HSA. The HSA-GA complex therefore emerges as a possible platform for the crystallographic study of specific HSA-drug interactions and of the influence exerted by the presence of fatty acids.

Place, publisher, year, edition, pages
2008. Vol. 64, no Pt 2, 64-69 p.
Keyword [en]
human serum albumin, GA module, bacterial surface proteins, naproxen, albumin binding, fatty acids
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-96604DOI: 10.1107/S174430910706770XISI: 000252817400002OAI: oai:DiVA.org:uu-96604DiVA: diva2:171238
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Evasion and Attack: Structural Studies of a Bacterial Albumin-binding Protein and of a Cephalosporin Biosynthetic Enzyme
Open this publication in new window or tab >>Evasion and Attack: Structural Studies of a Bacterial Albumin-binding Protein and of a Cephalosporin Biosynthetic Enzyme
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the crystal structures of two proteins in the context of combatting bacterial infections. The GA module is a bacterial albumin-binding domain from a surface protein expressed by pathogenic strains of the human commensal bacterium Finegoldia magna. The structure of the GA module in complex with human serum albumin (HSA) provides insights into bacterial immune evasion, where pathogenicity is acquired by the bacterial cell through the ability to coat (and disguise) itself with serum proteins. The structure shows binding of the GA module to HSA in the presence of fatty acids, and reveals interactions responsible for the host range specificity of the invading bacterium. The complex resulting from binding of the GA module to HSA readily forms stable crystals that permit structural studies of drug binding to HSA. This was exploited to study the specific binding of the drug naproxen to the albumin molecule.

Antibiotics play a major role in controlling infections by attacking invading bacteria. The enzyme deacetylcephalosporin C acetyltransferase (DAC-AT) catalyses the last step in the biosynthesis of the beta-lactam antibiotic cephalosporin C, one of the clinically most important antibiotics in current use. The enzyme uses acetyl coenzyme A as cofactor to acetylate a biosynthetic intermediate. Structures of DAC-AT in complexes with reaction intermediates have been determined. The structures suggest that the acetyl transfer reaction proceeds through a double displacement mechanism, with acetylation of a catalytic serine by the cofactor through a suggested tetrahedral transition state, followed by acetyl transfer to the intermediate through a second suggested tetrahedral transition state. The structure of DAC-AT yields valuable information for the continued study of cephalosporin biosynthesis in the context of developing new beta-lactam compounds.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 382
Keyword
human serum albumin, GA module, albumin-binding, Finegoldia magna, deacetylcephalosporin C acetyltransferase, cephalosporin C, antibiotic, beta-lactam, biosynthesis, Acremonium chrysogenum, X-ray crystallography
National Category
Structural Biology
Identifiers
urn:nbn:se:uu:diva-8399 (URN)978-91-554-7062-3 (ISBN)
Public defence
2008-02-01, B22, Biomedical Centre, Husargatan 3, Uppsala, 13:00
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Supervisors
Available from: 2008-01-10 Created: 2008-01-10Bibliographically approved

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Acta Crystallographica. Section F: Structural Biology and Crystallization Communications
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