Table 1. List of imported resources, type and reference Name UniProt (2) RefSeq (3) Ensembl metazoa (11) Integr8 (14) CATH (1) Pfama (13) Superfamilya (17) SMARTa (18) Ensembl Variation (11) UniProt features (2) TMHMM v2.0a (19) Sega (20) Coilsa (21) Panthera (22) DisoPred2 (4) GO pathways (6) MINT (23) IntAct (24) GO cellular loc. (6) KEGG pathways (7) KEGG orthologue (7) GO molecular (6) UniProt descriptions (2) eggNOG (16) NCBI taxonomy (25) New? N N Y N N N N N Y Y (partly) Y N N N Y N N N N N N N Y Y N Nucleic Acids Research, 2010, Vol. 38, Database issue D297 Type SD SD SD/G G SF SF SF SF SF SF SF SF SF SF SF P P P P P MF MF MF MF T Description Protein database Protein database Genome assemblies UniProt-based genome sets Domain family classiﬁcation Domain family classiﬁcation Domain family classiﬁcation Domain family classiﬁcation Sequence polymorphisms Functional elements Transmembrane helices Low complexity regions Coiled-coil regions Protein family classiﬁcation Disordered regions Pathway descriptions Protein–protein interactions Protein–protein interactions Cellular locations. Pathway assignments Molecular function Molecular function Molecular function Molecular function Taxonomic hierarchy aObtained via SIMAP (26). If the resource has been added to Gene3D since 2008 it is marked as ‘Y’ for ‘New’. Types: ‘SD’: imported protein sequence databases; ‘G’: genome assemblies; ‘SF’: sequence feature annotation; ‘P’: metabolic, regulatory and biological pathways; ‘MF’: molecular function; ‘T’: taxonomy tree. and proﬁles built by using each sequence to seed a SAM Target-2K (9) iterative search (strategy 10). A mask was added to the resulting sequence alignment, so that only columns that align with the original seed sequence are used to build a proﬁle HMM with HMMER 3’s ‘hmmbuild’. The Gene3D v9 sequence database was generated by merging UniProt, RefSeq and Ensembl 55 (11), creating a set of 9.5 million distinct protein sequences; ‘hmmsearch’ was then used to ﬁnd matches with E-value <0.001. Once all signiﬁcant matches have been gathered, DomainFinder is used to resolve them into a set of conﬁ- dent domain assignments. DomainFinder has been signiﬁcantly redeveloped (version 3; paper submitted). This version signiﬁcantly reduces the number of false negatives (missed domains) by using a more sophisticated representative match selection protocol based around searching graphs of overlapping matches with the exact- weighted clique ﬁnding algorithm of Cliquer (12). This translated into a 15% increase in the number of domains conﬁdently identiﬁed by Gene3D in large-scale sequence databases. For Gene3D v9.0.0, a match overlap of 30 or less residues was permitted, while if a sub-graph of matches contained more than 5900 nodes, then the old algorithm was used to reduce computational time (<0.005% of all sequences aﬀected). In total, 9 050 048 domains were identiﬁed in 5 186 382 million sequences, a mean of 1.7 domains per annotated sequence, and an overall sequence coverage of 55%. By using the benchmark set generated for testing DomainFinder, we estimated the minimum and maximum bounds for the rate of false- positive predictions for Gene3D (for details see Supplementary Data) to be between 0.2% and 0.6% of all domains. However, many of these ‘false positives’ may signify complex relationships between two superfamilies or errors in the CATH classiﬁcation due to incomplete information. A NEW WEBSITE FOR LARGE AND SMALL QUERIES The Gene3D website supports a wide range of query terms, from protein and gene identiﬁers to superfamily codes, species names and function codes. It returns either a detailed description of the protein of interest or a summary view of the selected set of proteins. Previously, the size of a returned set of proteins was restricted to 5000, meaning that only subsets of the biggest superfamilies could be retrieved. The new site is now capable of retrieving annotations, species assignments and architectures for the huge P-loop hydrolase superfamily (34 050 300), containing over 530 000 domains in 440 000 sequences—although a few seconds can be required to render some of the results tabs in the browser. Both the single protein and protein collection (i.e. a family or genome) views present a similar set of integrated information grouped into ﬁve categories: (i) taxonomic and genome data; (ii) sequence features and domain architectures; (iii) molecular and biochemical function; (iv) interactions and pathways; and (v) sequence database cross-references. The querying system then allows the user to select identiﬁers—for instance, the