RESUMO
A three-dimensional model of PTTH-II has been constructed using interactive computer graphics and energy, minimisation techniques, assuming homology with porcine insulin, the structure of which has been determined by X-ray analysis. The model shows that PTTH-II can assume an insulin-like tertiary structure, which is compact with the exception of the sequence variable NH2-terminal amino acids of the B chain. Most of the hydrophobic core residues including A2 Ile, A6 Cys, A11 Cys, A16 Leu, A20 Cys, B11 Leu, B15 Leu and B19 Cys are identical in PTTH-II and insulins. The glycines at A1, B8 and B23 allow the chain to assume the characteristic tertiary interactions of the insulin fold and although polypeptide chains are shorter at the COOH-termini of the A and B chains and extended at the NH2-terminus of the B chain, the insulin-like tertiary structure can still be assumed. It is unlikely that PTTH-II forms either dimers or hexamers, characteristic of porcine and human insulin, and the model is consistent with the inability of PTTH-II to bind anti-insulin antibodies or insulin receptors. A hydrophobic surface region of PTTH-II may be involved in intermolecular actions of physiological relevance. We discuss the implications of our model for evolution of this family of hormones and growth factors.
Assuntos
Bombyx , Hormônios de Inseto , Insulina , Animais , Bombyx/genética , Gráficos por Computador , Humanos , Hormônios de Inseto/genética , Insulina/genética , Substâncias Macromoleculares , Modelos Moleculares , Conformação Proteica , Especificidade da EspécieRESUMO
Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common 'insulin fold' is probably adopted by all family members. Although the specificities of receptor binding are different, there is a possibility of co-evolution of polypeptides and their receptors.
Assuntos
Insulina/química , Receptor de Insulina/química , Sítios de Ligação , Evolução Biológica , Substâncias de Crescimento/química , Neuropeptídeos/química , Receptores de Superfície Celular/químicaRESUMO
Current ideas suggest that a conformational change in the insulin monomer may play an important part in its interaction with the insulin receptor. An investigation is reported in which analytical reversed-phase high-performance liquid chromatography of insulin analogues was used to investigate the solution conformation of the insulin monomer. The results are interpreted in terms of elution coefficients modified by the calculated surface accessibilities of individual residues. The results suggest a partial unfolding of the insulin monomer under the experimental conditions used, which is consistent with current ideas on the biologically active conformation of insulin.