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通过 X 射线晶体学和生物物理技术对胰岛素谷赖氨酸进行分子水平分析。

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

机构信息

Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2HA, UK.

Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK.

出版信息

Sci Rep. 2021 Jan 18;11(1):1737. doi: 10.1038/s41598-021-81251-2.

DOI:10.1038/s41598-021-81251-2
PMID:33462295
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7814034/
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.

摘要

本研究涉及赖脯胰岛素，一种在糖尿病管理中起重要作用的速效胰岛素类似物。我们应用了一系列方法，包括 X 射线晶体学和生物物理特性分析，以深入了解赖脯胰岛素的结构和功能。X 射线数据提供了分辨率为 1.26Å 的结构信息。晶体属于 H3 空间群，具有六边形（中心三角）细胞尺寸 a=b=82.44 和 c=33.65Å，在不对称单位中有两个分子。观察到 D21Glu 的独特位置，不在其他速效类似物中，指向内部而不是外部表面。这减少了与相邻分子的相互作用，从而增加了二聚体形式的偏好。沉降速度/平衡研究揭示了二聚体和六聚体/二六聚体的三元体系处于动态平衡中。这些新信息可能有助于更好地理解赖脯胰岛素的药代动力学和药效动力学行为，这可能有助于改善其速效作用的配方，并减少这种药物的副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0907/7814034/bbfaafc57ed0/41598_2021_81251_Fig7_HTML.jpg
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