To determine the general relation between the sequence and structure of variable domains of immunoglobulins we have carried out an analysis of their atomic structures, some 5300 different expressed sequences and the human germline gene segments. Variable domains are formed by two beta-sheets, packed face to face, and the inter-strand turns. Comparison of the different known structures shows that they have a core of 76 residues which has the same main-chain conformation in all structures. This common core contains almost all of the beta-sheet structure and three inter-strand turns. The regions that differ in conformation are the three hypervariable regions, three other inter-strand turns and a few adjacent residues. The 5300 expressed sequences currently known for variable domains were examined to determine the residues that occur at the 76 sites. Ignoring site conservations that occur for functional reasons, there are eight sites that have the same residue in almost all sequences; 12 that have one of a small group of very similar residues, and 52 where the chemical character of the residues is strongly conserved but not their volume. The role of residues at each site in the core was determined from the examination of their accessible surface areas, contacts, packing and buried side-chain hydrogen bonds. The most strongly conserved sites form the "deep" structure of the domain at the centre of the interface between the beta-sheets. It includes eight invariant sites and 11 sites that have one of a set of very similar residues. Around the deep structure there are buried hydrophobic residues that, in different variable domains, can differ greatly in volume. These differences in volume are accommodated by conformational changes in turn regions that are outside the common core. On the surface nearly all residues not involved in function or turn conformations strongly conserve hydrophilic or neutral residues. The implications of these results for the general relations between the sequence and structure of proteins are discussed.
Copyright 1998 Academic Press Limited.