Solution structures of the R6 human insulin hexamer,

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biophysics

Background:

• Insulin hexamers are crucial for insulin storage and release.
• Phenol stabilization influences insulin hexamer structure and dynamics.
• Understanding R6 insulin hexamer structure is key to its function.

Purpose of the Study:

• To determine the three-dimensional solution structure of the phenol-stabilized R6 insulin hexamer.
• To investigate the conformational flexibility of the Phe(B25) residue.
• To compare the solution structure with the crystal structure.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy.
• Restrained molecular dynamics simulations.
• Distance geometry and simulated annealing algorithms.

Main Results:

• Two distinct hexamer structures were identified in solution, differing in Phe(B25) orientation.
• The overall solution structure is compact, rigid, and symmetric, resembling the crystal structure.
• The B-chain alpha-helix extension in the R state is shorter in solution than in crystal structures.

Conclusions:

• The orientation of Phe(B25) does not significantly alter the overall hexamer structure.
• Solution structure reveals subtle differences in helix extension compared to crystal structures.
• Findings provide insights into insulin dynamics and receptor interactions.