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., …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
• Print ISSN: 2045-2322
• 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