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Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques
Coffey, Frank Morgan, Paul S
Coffey, Frank
Morgan, Paul S
Abstract
This study concerns glulisine, a rapid-acting insulin analogue that plays a fundamental role in diabetes management. We have applied a combination of methods namely X-ray crystallography, and biophysical characterisation to provide a detailed insight into the structure and function of glulisine. X-ray data provided structural information to a resolution of 1.26 A. Crystals belonged to the H3 space group with hexagonal (centred trigonal) cell dimensions a = b = 82.44 and c = 33.65 A with two molecules in the asymmetric unit. A unique position of D21Glu, not present in other fast-acting analogues, pointing inwards rather than to the outside surface was observed. This reduces interactions with neighbouring molecules thereby increasing preference of the dimer form. Sedimentation velocity/equilibrium studies revealed a trinary system of dimers and hexamers/dihexamers in dynamic equilibrium. This new information may lead to better understanding of the pharmacokinetic and pharmacodynamic behaviour of glulisine which might aid in improving formulation regarding its fast-acting role and reducing side effects of this drug.
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Date
2021
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Gillis, R.B., Solomon, H.V., Govada, L., Oldham, N.J., Dinu, V., Jiwani, S.I., Gyasi-Antwi, P., Coffey, F., Meal, A., Morgan, P.S., Harding, S.E., Helliwell, J.R., Chayen, N.E. and Adams, G.G. (2021) 'Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques', Scientific reports, 11(1), pp. 1737. doi: https://dx.doi.org/10.1038/s41598-021-81251-2.