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

DOI: 10.1038/s41598-021-81251-2 DOI Help

Authors: Richard B. Gillis (University of Nottingham) , Hodaya V. Solomon (Imperial College London) , Lata Govada (Imperial College London) , Neil J. Oldham (University of Nottingham) , Vlad Dinu (University of Nottingham) , Shahwar Imran Jiwani (University of Nottingham) , Philemon Gyasi-Antwi (University of Nottingham) , Frank Coffey (University of Nottingham) , Andy Meal (University of Nottingham) , Paul S. Morgan (University of Nottingham) , Stephen E. Harding (University of Nottingham; Universitetet I Oslo) , John R. Helliwell (University of Manchester) , Naomi E. Chayen (Imperial College London) , Gary G. Adams (University of Nottingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 11

State: Published (Approved)
Published: January 2021

Open Access Open Access

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 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.

Journal Keywords: Biophysical chemistry; Diabetes; Mass spectrometry; Molecular conformation; X-ray crystallography

Diamond Keywords: Diabetes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 27/01/2021 10:50

Documents:
s41598-021-81251-2.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)