Description of the experimental procedure. Surface functional sites are automatically located and annotated as described in Methods. Surface clefts, identified by means of SURFNET, are filtered using a volume threshold, and annotated for the binding ability or for the presence of a functional motif from the PROSITE or ELM databases. This library (the SURFACE database) is used to scan a non-redundant collection of protein structures; a semi-automated procedure is used to define conditions for which the structural similarity implies also a functional relationship. Finally, the SURFACE database is used to analyze a list of proteins with unknown function from structural genomic projects, obtaining in several cases significant similarities that could have not been spotted through sequence or fold similarity.