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

Autor: Gillis RB; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK. richard.gillis@nottingham.ac.uk., Solomon HV; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK., Govada L; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK., Oldham NJ; School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK., Dinu V; National Centre for Macromolecular Hydrodynamics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK., Jiwani SI; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK., Gyasi-Antwi P; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK., Coffey F; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK., Meal A; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK., Morgan PS; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK., Harding SE; National Centre for Macromolecular Hydrodynamics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK.; Universitetet I Oslo, St. Olavs plass, Postboks 6762, 0130, Oslo, Norway., Helliwell JR; Department of Chemistry, University of Manchester, Manchester, M13 9PL, UK., Chayen NE; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK. n.chayen@imperial.ac.uk., Adams GG; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK. gary.adams@nottingham.ac.uk.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jan 18; Vol. 11 (1), pp. 1737. Date of Electronic Publication: 2021 Jan 18.
DOI: 10.1038/s41598-021-81251-2
Abstrakt: 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 Å. Crystals belonged to the H3 space group with hexagonal (centred trigonal) cell dimensions a = b = 82.44 and c = 33.65 Å 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.
Databáze: MEDLINE
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