Steric requirements at position B12 for high biological activity in insulin

A study was conducted on the spatial requirements of the B12 region in insulin and the biological properties of synthesized insulin analogues in which other hydrophobic amino acid residues replaced the B11 and B12 residues. The analogues that resulted from alpha-aminoisobutyric acid, D-Ala and Phe substitution of B12 Val were found to exhibit biological activities of 8.5%, 2% and 0.2%, respectively compared to natural insulin, while the analogue formed by inverting the B11-B12 sequence, had 3.3% activity. Results indicate that the B12 position's Val residue plays a role in the special side-chain packing requirements that contributes to insulin's structural stability.