Similar results were previously shown by mutating the residue corresponding to Asp166 in EGFR and showing retained biological function. Another example of atypical active kinases are the WNK kinases, lacking the ultra-conserved Lys72 whereas a lysine located elsewhere in the sequence assumes the role of Lys72. Also, recent work by Manning and co-workers provides evidence of rich diversity of kinase families in the marine metagenome, with several families lacking one or more key catalytic motifs previously identified in studies on eukaryotic PKL kinases. Therefore, as summarised recently by Taylor, ����It is difficult to say unambiguously given kinase will be inactive����. Manning and colleagues have performed structure comparison of an inactive pseudo kinase and a closely homologous active kinase counterpart. They have discussed various alterations in the conserved kinase motifs and concluded that provided the ATP binding G-loop is functional, other conserved motifs may be at times compensated for, if missing or altered. For very distantly related homologues, the sequence alignment details are known to be less reliable than the overall detection of homology stemming from significant similarity. Thus, some of our definitions of SELO kinase active site short motifs, e.g. the location of the classic Lys 72, may be erroneous. Also, even if the kinase function Xanthohumol predicted for SELO proteins is true, it is not straightforward to predict the substrate. Among the top-ranking hits for SELO, there were both lipopolysaccharide kinases and protein kinases. However, the lipopolysaccharide kinase prediction seems less likely, Sibutramine HCl because this family lacks the DFG/ DYG motif responsible for the magnesium ion binding in the catalytic site. This motif is strictly conserved among protein kinases, as well as among SELO homologues. It has been previously demonstrated that many free-living marine microbes possess homologues of virulence genes, hence they propose a hypothesis that disease �C related genes may be sometimes originating from marine bacteria invading eukaryotic hosts in the marine environment. This adds to the appeal of studying protein families with atypical phylogenetic distribution, such as the SELO/ydiU family. The challenge of turning a structure prediction into a useful function prediction involves specifying particular suggestions for experimental validation. It is even more challenging to turn the molecular function prediction into a biological process prediction, the latter usually being not directly linked to protein structure.