Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta. The region 1-16 of Abeta can be considered the minimal zinc-binding domain and contains two aspartates subject to protein aging. The influence of zinc binding and protein aging related modifications on the conformation of this region of Abeta is of importance given the potentiality of this domain to constitute a therapeutic target, especially for immunization approaches. In this study, we determined from NMR data the solution structure of the Abeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on Abeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, Abeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results are discussed here with regard to Abeta fibrillogenesis and the potentiality of the region 1-16 of Abeta to be used as a therapeutic target.

No abstract

PAC1 receptor is abundant in the CNS and plays an important role in neuronal survival. To identify the molecular determinants and the conformational components responsible for the activation of the PAC1 receptor, we performed a SAR study focusing on the N-terminal domain of its endogenous ligand, PACAP. This approach revealed that residues Asp(3) and Phe(6) are key elements of the pharmacophore of the PAC1 receptor. This study, supported by NMR structural analyses, suggests that the N-terminal tail of PACAP (residues 1 to 4) adopts a specific conformation similar to a turn when it activates the PAC1 receptor. Moreover, the integrity of the alpha-helix conformation observed at positions 5 to 7 appears crucial to allow the binding of PACAP. Characterization of analogues led to the identification of several superagonists, such as [Bip(6)]PACAP27, and of a new potent PAC1 receptor antagonist, [Sar(4)]PACAP38. The bioactive conformation inferred from this SAR study could constitute an appropriate molecular scaffold supporting the design of nonpeptidic PAC1 receptor agonists.