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Metallo-b-lactamases as model zn enzymes

Objective

A full understanding of the structure-activity relationship in proteins is becoming a major challenge of the post-genomic area. Solving this problem requires multidisciplinary studies in which the functional characteristics of a protein are analyzed and correlated with its structural features. Young scientists are needed who can master various subsets of the large number of techniques involved in this approach. Metallo-Beta-lactamases offer a nearly ideal object for this type of research. They constitute a rather diverse family of enzymes with only a very small number of residues strictly conserved in all proteins but the known 3-D structures are clearly related. Similarly, very different specificity profiles have been observed. Depending upon the enzyme, the most active form contains one or two Zn ^++ ions. These can be replaced by other transition metal divalent cations (Co^++, Cd), with concomitant modifications of the activity profiles. The projected studies will rest on the most up-to-date techniques for the analysis of the protein-metal, protein-substrate and protein-inhibitor interaction and for structural analyses. In consequence, significant technological improvement can be expected and it will be possible to apply this new knowledge to other Zn-hydrolases, some of which are of great biological and clinical interest, for instance the matrix metalloproteases. Finally, the emergence of metallo-Beta-lactamase-producing pathogenic strains represents a worrying clinical problem because they can hydrolyze carbapenems, often utilized as last-resort antibiotics and escape the action of the in activators designed against the active-site-serine Beta- lactamases. The genes encoding several MBLs are plasmid or transposon-borne, which makes their spreading by selective pressure a frightening possibility. For this reason, an important part of the project will be devoted to the search for specific MBL inhibitors which should ideally be active on all MB

Funding Scheme

NET - Research network contracts
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Coordinator

UNIVERSITE DE LIEGE
Address
Allée De La Chimie 3, Bètiment B6
4000 Liege
Belgium

Participants (9)

AMURA LIMITED
United Kingdom
Address
St John's Innovation Centre, Cowley Road
CB4 0WS Cambridge
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France
Address
Rue Jules Horowitz 41
38027 Grenoble
SAARLAND UNIVERSITY
Germany
Address
Im Stadtwald
151150 Saarbruecken
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
Address
South Parks Road
OX1 3QT Oxford
THE ROYAL VETERINARY AND AGRICULTURAL UNIVERSITY
Denmark
Address
40,Thorvaldsensvej 40
1871 Frederisksberg
UNIVERSIT DEGLI STUDI DI SIENA
Italy
Address
Via Bracci, 16
53100 Siena
UNIVERSITY OF LEICESTER
United Kingdom
Address
The Adrian Building, University Road
LE1 7RH Leicester
UNIVERSITÀ DEGLI STUDI - L'AQUILA
Italy
Address
Via Vetoio
67010 Assergi
University of Huddersfield
United Kingdom
Address
Queensgate
HD1 3DH Huddersfield