ABSTRACT
Symmetrical features were observed in the amino acid sequences of some biologically active peptides. It is suggested that this approximate symmetry is reflected in the conformations of the peptides at their respective biological receptors, and has arisen by natural selection as both peptides and receptors evolved to optimise their mutual fit. It follows that the binding site for each peptide at its receptor would share the same symmetry element. This would arise if the peptide binds to two symmetrically related similar or identical submits in the receptor.
Subject(s)
Peptides , Receptors, Cell Surface , Amino Acid Sequence , Angiotensin II , Binding Sites , Bradykinin , Glucagon , Gonadotropin-Releasing Hormone , Molecular Conformation , Protein Conformation , Thyrotropin-Releasing HormoneABSTRACT
Insulin is a small globular protein with a well defined tertiary structure which is closely similar in all species with the exception of certain hystricomorphs such as the guinea pig. Insulin-like growth factor is homologous with insulin and probably has an insulin-like tertiary structure. In contrast glucagon is not a globular protein. It exists as an equilibrium population of conformers with low helix content at physiological concentrations but attains a largely helical conformation on association to trimers. The receptor binding of insulin depends critically on the correct three-dimensional juxtaposition of groups (A1, A21, B25, etc) and involves both hydrophobic and polar interactions. In insulin-like growth factor part of the insulin receptor region is thought to be buried in extra peptide, so explaining its weak binding to insulin receptors. In contrast the glucagon receptor complex probably involves largely hydrophobic contacts which are possible when a helical conformer is formed.
Subject(s)
Glucagon/metabolism , Insulin/metabolism , Receptor, Insulin , Receptors, Cell Surface , Adipose Tissue/metabolism , Animals , Models, Molecular , Proinsulin , Protein Binding , Protein Conformation , Rats , Receptor, Insulin/metabolism , Receptors, Cell Surface/metabolism , X-Ray DiffractionABSTRACT
X-ray analysis of the pancreatic hormone glucagon shows that in crystals the polypeptide adopts a mainly helical conformation, which is stabilised by hydrophobic interactions between molecules related by threefold symmetry. A model is presented in which the glucagon molecule exists in dilute solutions as an equilibrium population of conformers with little retention of conformers with little retention of structure, and in which the helical conformation is stablised by hydrophobic interactions either as an oligomer or as a complex with the receptor.
