Article (Scientific journals)
Crystal structure of the narrow-spectrum OXA-46 class D β-lactamase: Relationship between active-site lysine carbamylation and inhibition by polycarboxylates
Docquier, Jean-Denis; Benvenuti, M.; Calderone, V. et al.
2010In Antimicrobial Agents and Chemotherapy, 54 (5), p. 2167-2174
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Keywords :
Pseudomonas aeruginosa; Amino Acid Sequence; Anions; Carboxylic Acids; Catalytic Domain; Conserved Sequence; Crystallography, X-Ray; Lysine; Molecular Sequence Data; Oxalates; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Structure, Tertiary; Structure-Activity Relationship; Tartrates
Abstract :
[en] Class D β-lactamases represent a heterogeneous group of active-site serine β-lactamases that show an extraordinary panel of functional features and substrate profiles, thus representing relevant models for biochemical and structural studies. OXA-46 is a narrow-spectrum enzyme belonging to the OXA-2 subgroup which was found in a Pseudomonas aeruginosa clinical isolate from northern Italy. In this work, we obtained the three-dimensional structure of OXA-46, which shows the overall fold of active serine β-lactamases and a dimeric quaternary structure. Significant differences with currently available structures of class D β-lactamases were found in the loops located close to the active site, which differ in length and conformation. Interestingly, the three subunits present in the asymmetric unit showed some structural heterogeneity, only one of which presented a carbamylated lysine recognized as an important functional feature of class D enzymes. The carbamylation state of residue Lys75 appeared to be associated with different shapes and dimensions of the active site. Moreover, a tartrate molecule from the crystallization buffer was found in the active site of the noncarbamylated subunits, which interacts with catalytically relevant residues. The OXA-46 crystal asymmetric units thus interestingly present the structures of the free carbamylated active site and of the ligand-bound uncarbamylated active site, offering the structural basis for investigating the potential of new scaffolds of β-lactamase inhibitors. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Disciplines :
Biochemistry, biophysics & molecular biology
Microbiology
Author, co-author :
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Benvenuti, M.;  Dipartimento di Chimica, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy
Calderone, V.;  Dipartimento di Chimica, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy, Magnetic Resonance Center CERM, Università di Firenze, I-50019, Sesto Fiorentino, Italy
Giuliani, F.;  Dipartimento di Biologia Molecolare, Laboratorio di Fisiologia e Biotecnologia dei Microrganismi, Università di Siena, I-53100, Siena, Italy
Kapetis, D.;  Dipartimento di Chimica, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy
De Luca, F.;  Dipartimento di Biologia Molecolare, Laboratorio di Fisiologia e Biotecnologia dei Microrganismi, Università di Siena, I-53100, Siena, Italy
Rossolini, G. M.;  Dipartimento di Biologia Molecolare, Laboratorio di Fisiologia e Biotecnologia dei Microrganismi, Università di Siena, I-53100, Siena, Italy, U.O.C. Microbiologia e Virologia, Università di Siena, I-53100, Siena, Italy
Mangani, S.;  Dipartimento di Chimica, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy, Magnetic Resonance Center CERM, Università di Firenze, I-50019, Sesto Fiorentino, Italy
Language :
English
Title :
Crystal structure of the narrow-spectrum OXA-46 class D β-lactamase: Relationship between active-site lysine carbamylation and inhibition by polycarboxylates
Publication date :
2010
Journal title :
Antimicrobial Agents and Chemotherapy
ISSN :
0066-4804
eISSN :
1098-6596
Publisher :
American Society for Microbiology, Washington, United States - District of Columbia
Volume :
54
Issue :
5
Pages :
2167-2174
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 20 November 2020

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