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
Coordinator
4000 Liege
Belgium
Participants (9)
CB4 0WS Cambridge
38027 Grenoble
151150 Saarbruecken
OX1 3QT Oxford
1871 Frederisksberg
53100 Siena
LE1 7RH Leicester
67010 Assergi
HD1 3DH Huddersfield
