Protein Engineering, Vol. 15, No. 8, 697-705,
August 2002
© 2002 Oxford University Press
Conserved water molecules in MHC class-I molecules and their putative structural and functional roles
1 Service de Conformation de Macromolécules Biologiques, Centre de Biologie Structurale et Bioinformatique, Université Libre de Bruxelles,av. F.D. Roosevelt 50, CP160/16, B-1050 Brussels, Belgium and 2 European Bioinformatics Institute (EBI), Genome Campus, Hinxton, Cambridge CB10 1SD, UK
A set of conserved water positions making direct contacts with the 
1 and 2 domains of the MHC class-I protein was identified by a cluster analysis in 12 high-resolution crystal structures of proteins from different allele types and different species, comprising human, mouse and rat. The analysis revealed a total of 63 clusters, corresponding to water molecules, whose positions are conserved in half or more of the analyzed structures. Analysis of these clusters shows that the most conserved water positions—those appearing in the largest fraction of the structures—were also the most accurately defined, as measured by their normalized crystallographic B-factor. Not too surprisingly, these positions displayed better overlap and formed more H-bonds with the protein. In a second part of this work, a detailed analysis is presented of three of the most conserved water positions and their putative structural and functional roles are discussed. The most highly conserved of the three appears to play an important role in stabilizing the conformation of a twisted ß-turn between residues 118 and 122 (numbering of HLA-B3501, PDB code 1A1N). An equivalent water molecule was found to be associated with a similar ß-turn in 43 unrelated structures surveyed in the PDB, leading to the suggestion that this water molecule plays an important structural role in this type of turn. The second water molecule makes hydrogen bonds with residues lining pocket B in the peptide-binding groove and is suggested to play a role in modulating peptide recognition. The third highly conserved water molecule is located at the first kink of the 2 helix, possibly playing a role in determining the position of the N-terminal segment of that helix, which also carries side chains in contact with the bound peptide. This information on conserved water positions in MHC class-I molecules should be helpful in modeling interactions with bound peptide antigens and in designing new peptides with tailor-made affinities.
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