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Crystal structure and biological implications of a bacterial albumin binding module in complex with human serum albumin
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2004 In: Journal of Biological Chemistry, ISSN 1083-351X, Vol. 279, no 41, 42924-42928 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 279, no 41, 42924-42928 p.
Identifiers
URN: urn:nbn:se:uu:diva-96603OAI: oai:DiVA.org:uu-96603DiVA: diva2:171237
Available from: 2008-01-10 Created: 2008-01-10Bibliographically 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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Available from: 2008-01-10 Created: 2008-01-10Bibliographically approved

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