R. Bader et al., Using structural information of peptides, derived from NMR spectroscopy, in pharmaceutical chemistry, CHIMIA, 54(11), 2000, pp. 627-632
The significance of information gained from the solution structure of pepti
des for pharmaceutical research is demonstrated with two examples: the neur
opeptide Y (N PY) hormone system and a undecapeptide designed for use as a
chemical sensor. In the case of NPY, the structure of the homodimer and the
mode of membrane association was determined. Thereby, it was discovered th
at the membrane/NPY interface is formed by the same hydrophobic residues th
at constitute the homodimer interface. Furthermore, in the membrane-bound s
tate, the C-terminal helix is stabilized, which is of special functional im
portance for the C-terminal tetrapeptide. Receptor-subtype specificity of N
PY mutants may be explained through pre-orientation of residues relative to
the different membrane compartments. In the case of the undecapeptide desi
gned for use in a chemical sensor, structural information from NMR helped u
s to design and optimize a peptide whose unligated form is unstructured in
solution but adopts a unique helical fold upon addition of sulfate. The sul
fate binding pocket is formed by the N-terminal first turn.