Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques

Gillis, Richard B.; Solomon, Hodaya V.; Govada, Lata; Oldham, Neil J.; Dinu, Vlad; Jiwani, Shahwar Imran; Gyasi-Antwi, Philemon; Coffey, Frank; Meal, Andy; Morgan, Paul S.; Harding, Stephen E.; Helliwell, John R.; Chayen, Naomi E.; Adams, Gary G.

Abstract

© 2021, The Author(s). 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 1.26Å. Crystals belonged to the H3 space group with hexagonal (centred trigonal) cell dimensions a = b = 82.44 and c = 33.65Å 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.

Citation

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., & Adams, G. G. (2021). Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques. Scientific Reports, 11(1), Article 1737. https://doi.org/10.1038/s41598-021-81251-2

• Journal Article Type: Article
• Acceptance Date: Dec 9, 2020
• Online Publication Date: Jan 18, 2021
• Publication Date: Jan 18, 2021
• Deposit Date: Feb 3, 2021
• Publicly Available Date: Feb 3, 2021
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 1
• Article Number: 1737
• DOI: https://doi.org/10.1038/s41598-021-81251-2
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/5289753
• Publisher URL: https://www.nature.com/articles/s41598-021-81251-2