TITLE

Crystallographic characterization of two novel crystal forms of human insulin induced by chaotropic agents and a shift in pH

AUTHOR(S)
Norrman, Mathias; Schluckebier, Gerd
PUB. DATE
January 2007
SOURCE
BMC Structural Biology;2007, Vol. 7, p83
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Insulin is a therapeutic protein that is widely used for the treatment of diabetes. Its biological function was discovered more than 80 years ago and it has since then been characterized extensively. Crystallization of the insulin molecule has always been a key activity since the protein is often administered by subcutaneous injections of crystalline insulin formulations. Over the years, insulin has been crystallized and characterized in a number of crystal systems. Results: Interestingly, we have now discovered two new crystal forms of human insulin. The crystals were obtained when the two chaotropic agents, urea and thiocyanate were present in the crystallization experiments, and their structures were determined by X-ray crystallography. The crystals belong to the orthorhombic and monoclinic crystal systems, with space groups C2221 and C2 respectively. The orthorhombic crystals were obtained at pH 6.5 and contained three insulin hexamers in R6 conformation in the asymmetric unit whilst the monoclinic C2 crystals were obtained at pH 7.0 and contained one R6 hexamer in the asymmetric unit. Common for the two new crystals is a hexamer-hexamer interaction that has not been found in any of the previous crystal forms of insulin. The contacts involve a tight glutamate-glutamate interaction with a distance of 2.3 Ã… between groups. The short distance suggests a low barrier hydrogen bond. In addition, two tyrosine-tyrosine interactions occupying a known phenol binding pocket contribute to the stabilization of the contacts. Within the crystals, distinct binding sites for urea were found, adding further to the discussion on the role of urea in protein denaturation. Conclusion: The change in space group from C2221 to C2 was primarily caused by an increase in pH. The fewer number of hexamer-hexamer interactions comprising the short hydrogen bond in the C2 space group suggest that pH is the driving force. In addition, the distance between the two glutamates increases from 2.32 Ã… in the C2221 crystals to 2.4 Ã… in the C2 crystals. However, in both cases the low barrier hydrogen bond and the tyrosine-tyrosine interaction should contribute to the stability of the crystals which is crucial when used in pharmaceutical formulations.
ACCESSION #
34976789

 

Related Articles

  • Antihyperglycaemic use up but varied in Europe.  // PharmacoEconomics & Outcomes News;10/21/2006, Issue 514, p6 

    The article reveals that the overall use of antihyperglycaemic drugs has increased over time in Europe, but large differences in use between countries are apparent, according to a study conducted by a multinational group of researchers. In England and Germany, the use of insulin doubled over the...

  • Challenge calls for discovery of new insulin.  // Endocrine Today;Oct2011, Vol. 9 Issue 10, p19 

    The article focuses on the 100,000 U.S. dollar challenge announced by the Juvenile Diabetes Research Foundation and InnoCentive to look for innovative ways to approach the discovery and development of a glucose-responsive insulin to treat diabetes.

  • Clinical Q & A.  // Drug Topics;11/20/2000, Vol. 114 Issue 22, p41 

    Answers a question on the difference of insulin glargine and insulin aspart from the older insulins. Characteristic of diabetes mellitus (DM); Insulin products used in the treatment of DM; Number of people in the United States affected by the disease.

  • Improved Postprandial Glycemic Control With Insulin Aspart. Lindholm, Anders; McEwen, John; Riis, Anders P. // Diabetes Care;May99, Vol. 22 Issue 5, p801 

    Presents information on a study which compared the postprandial serum glucose control after administration of insulin aspart, a rapid-acting insulin analog, with that of unmodified human insulin in patients with type one diabetes. Research design and methods; Results; Conclusions.

  • What About Diabetes Drugs?  // Prevention;May2012, Vol. 64 Issue 5, p38 

    The article offers information on drugs indicated for treating type 2 diabetes. Metformin is the most common drug prescribed to diabetics. Gastric upset is the usual side effect associated with the drug. Victoza, a new diabetes drug, is a noninsulin medication that can be taken daily....

  • Insulin: A Never-ending Evolution. Dinsmoor, Robert S. // Countdown;Spring2001, Vol. 22 Issue 2, p46 

    Focuses on insulin, a protein used to treat diabetes. History of insulin and how it's relationship with glucose; Way that insulin works in the body; Technological advances made in insulin research; Details of insulin analogs; Efforts of manufacturers to explore alternative methods for...

  • The Vanishing Animal-Source Insulins.  // Countdown;Spring2001, Vol. 22 Issue 2, p47 

    Discusses how many people have encountered problems with human insulin. Use of animal insulin as an alternative; Incidence of hypoglycemia unawareness among those who switch from animal insulin to human insulin; Potential flaws in studies relating to insulin and hypoglycemia; Comparison of...

  • Rapid and Long-Acting Analogues as an Approach to Improve Insulin Therapy: An Evidence-Based Medicine Assessment. Heise, Tim; Heineman, Lutz // Current Pharmaceutical Design;Sep2001, Vol. 7 Issue 14, p1303 

    This review summarizes the results of clinical trials with the currently available insulin analogues (i.e., insulin lispro, insulin aspart, and insulin glargine) and evaluates their clinical benefit applying the standards of evidence-based medicine. All analogues show a more physiological...

  • Basalog® is similar to Lantus® in producing glycemic control in patients with type 1 diabetes mellitus on multiple daily insulin regimens. Verma, M.; Hazra, P.; Iyer, H.; Arun, A.; Akundi, S.; Dixit, M. N.; Eswaraiah, A.; Prasanna, C. G.; Atignal, A. // International Journal of Diabetes in Developing Countries;Feb2011, Vol. 31 Issue 1, p26 

    This study was performed to compare the insulin glargine produced by two different manufacturers. The study determines the efficacy and safety of a new insulin glargine (Basalog®) having the same amino-acid sequence as Lantus® in patients with type 1 diabetes mellitus on multiple daily...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics