(A) Front page of the COMPASS server. The main section allows the user to submit the query (by pasting in the window or by specifying the file), to choose the search database, and (if needed) to enter the email address to receive the results. The section of input processing options allows the user to choose whether a PSI-BLAST run is needed to enrich the query profile with additional sequence homologs and to define the parameters of profile construction. The section of search options can be used to adjust the main parameters of the search. The section of output options allows for flexible formatting of the search results. A brief explanation of each option is available by clicking on the option's name. Additional sections include the links to more detailed documentation and to the FTP page with standalone COMPASS package. (B) Search results for uncharacterized PFAM DUF185 as a query, supporting the structure and function prediction for this family. The list of hits among SCOP domains consistently includes members of the same superfamily of S-adenosyl-l-methionine-dependent methyltransferases (SAM-Mtases) (c.66.1). (C) Example of profile-profile alignment. The header includes brief information about the hit: database identifier, protein description, full length of the MSA (‘length’), the length of the profile after purging positions with high gap content (‘filtered length’), effective number of sequences as a characteristic of sequence divergence within MSA (‘Nef f ’), followed by COMPASS score and E-value. In this example, the top and consensus sequences for compared profiles are displayed. Position matches with positive scores are marked by ‘+’, identical residues in the two consensus sequences are marked by the residue symbol. Invariant glutamates of Motifs I and II (39) involved in ligand binding are marked with red dots, glycine-rich motif is circled. D: A recently solved structure for a member of DUF185 family (PDB ID 1zkd) confirms our prediction. Side chains of the invariant glutamate residues are shown in red, glycine-rich loop is circled.

Search results for PFAM DUF519 suggest that this family possesses the structural fold of SAM-Mtases. (A) DUF519 is used as a query for the COMPASS search against the databases of PSI-BLAST alignments (iteration 3) for SCOP representatives. The COMPASS alignment between the query and the detected homolog (domain 1qyrA) includes characteristic motifs of the SAM-Mtase superfamily. In this example, only consensus sequences are displayed. Positions corresponding to the conserved acidic residues of Motifs I and II (39) are marked with red dots. The region of the SAM-binding loop is circled. (B) Multiple alignment including representatives from DUF519 (top) and 1qyrA homologs (bottom). Sequences are denoted by NCBI GI numbers. Positions corresponding to conserved acidic residues of SAM-Mtase are marked with red dots. The region of the ligand-binding loop is marked with a line. Invariant residues are boxed in black. Uncharged residues (all amino acids except D, E, K, R) in mostly hydrophobic sites are highlighted in yellow; non-hydrophobic residues (all amino acids except W, F, Y, M, L, I, V) at mostly hydrophilic sites are highlighted in light gray. The secondary structure of 1qyrA is shown below the alignment, with α-helices and β-strands displayed as cylinders and arrows, respectively.