Richard B Gillis1, Hodaya V Solomon2, Lata Govada2, Neil J Oldham3, Vlad Dinu4, Shahwar Imran Jiwani5, Philemon Gyasi-Antwi5, Frank Coffey5, Andy Meal5, Paul S Morgan5, Stephen E Harding4,6, John R Helliwell7, Naomi E Chayen8, Gary G Adams9. 1. Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK. richard.gillis@nottingham.ac.uk. 2. Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK. 3. School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK. 4. National Centre for Macromolecular Hydrodynamics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK. 5. Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK. 6. Universitetet I Oslo, St. Olavs plass, Postboks 6762, 0130, Oslo, Norway. 7. Department of Chemistry, University of Manchester, Manchester, M13 9PL, UK. 8. 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. 9. Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK. gary.adams@nottingham.ac.uk.
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.
This study concerns glulisine, a rapid-acting n class="Gene">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.
Authors: Brandon M Teska; Javier Alarcón; Ronald J Pettis; Theodore W Randolph; John F Carpenter Journal: J Pharm Sci Date: 2014-06-06 Impact factor: 3.534
Authors: Gary G Adams; Andrew Meal; Paul S Morgan; Qushmua E Alzahrani; Hanne Zobel; Ryan Lithgo; M Samil Kok; David T M Besong; Shahwar I Jiwani; Simon Ballance; Stephen E Harding; Naomi Chayen; Richard B Gillis Journal: PLoS One Date: 2018-03-29 Impact factor: 3.240
Authors: Lucie Kosinová; Václav Veverka; Pavlína Novotná; Michaela Collinsová; Marie Urbanová; Nicholas R Moody; Johan P Turkenburg; Jiří Jiráček; Andrzej M Brzozowski; Lenka Žáková Journal: Biochemistry Date: 2014-05-22 Impact factor: 3.162