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

Programme(s)

• FP5-HUMAN POTENTIAL - Programme for research, technological development and demonstration on "Improving the human research potential and the socio-economic knowledge base" (1998-2002)

Funding Scheme

Coordinator

Participants (9)