1uz9: Difference between revisions
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==Overview== | ==Overview== | ||
The addition of specific bulky hydrophobic groups to the insulin molecule, provides it with affinity for circulating serum albumin and enables it to, form soluble macromolecular complexes at the site of subcutaneous, injection, thereby securing slow absorption of the insulin analogue into, the blood stream and prolonging its half-life once there. N-Lithocholic, acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has, been crystallized and the structure determined by X-ray crystallography at, 1.6 A resolution to explore the molecular basis of its assembly. The unit, cell in the crystal consists of an insulin hexamer containing two zinc, ions, with two m-cresol molecules bound at each dimer-dimer interface, stabilizing an R(6) conformation. Six covalently bound lithocholyl groups, are arranged symmetrically around the outside of the hexamer. These form, specific van der Waals and hydrogen-bonding interactions at the interfaces, between neighboring hexamers, possibly representing the kinds of, interactions which occur in the soluble aggregates at the site of, injection. Comparison with an equivalent nonderivatized native insulin, hexamer shows that the addition of the lithocholyl group disrupts neither, the important conformational features of the insulin molecule nor its, hexamer-forming ability. Indeed, binding studies show that the affinity of, N-lithocholyl insulin for the human insulin receptor is not significantly, diminished. | The addition of specific bulky hydrophobic groups to the insulin molecule, provides it with affinity for circulating serum albumin and enables it to, form soluble macromolecular complexes at the site of subcutaneous, injection, thereby securing slow absorption of the insulin analogue into, the blood stream and prolonging its half-life once there. N-Lithocholic, acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has, been crystallized and the structure determined by X-ray crystallography at, 1.6 A resolution to explore the molecular basis of its assembly. The unit, cell in the crystal consists of an insulin hexamer containing two zinc, ions, with two m-cresol molecules bound at each dimer-dimer interface, stabilizing an R(6) conformation. Six covalently bound lithocholyl groups, are arranged symmetrically around the outside of the hexamer. These form, specific van der Waals and hydrogen-bonding interactions at the interfaces, between neighboring hexamers, possibly representing the kinds of, interactions which occur in the soluble aggregates at the site of, injection. Comparison with an equivalent nonderivatized native insulin, hexamer shows that the addition of the lithocholyl group disrupts neither, the important conformational features of the insulin molecule nor its, hexamer-forming ability. Indeed, binding studies show that the affinity of, N-lithocholyl insulin for the human insulin receptor is not significantly, diminished. | ||
==Disease== | |||
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], Hyperproinsulinemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], MODY, one form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: insulin family]] | [[Category: insulin family]] | ||
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Revision as of 20:33, 12 November 2007
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CRYSTALLOGRAPHIC AND SOLUTION STUDIES OF N-LITHOCHOLYL INSULIN: A NEW GENERATION OF PROLONGED-ACTING INSULINS.
OverviewOverview
The addition of specific bulky hydrophobic groups to the insulin molecule, provides it with affinity for circulating serum albumin and enables it to, form soluble macromolecular complexes at the site of subcutaneous, injection, thereby securing slow absorption of the insulin analogue into, the blood stream and prolonging its half-life once there. N-Lithocholic, acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has, been crystallized and the structure determined by X-ray crystallography at, 1.6 A resolution to explore the molecular basis of its assembly. The unit, cell in the crystal consists of an insulin hexamer containing two zinc, ions, with two m-cresol molecules bound at each dimer-dimer interface, stabilizing an R(6) conformation. Six covalently bound lithocholyl groups, are arranged symmetrically around the outside of the hexamer. These form, specific van der Waals and hydrogen-bonding interactions at the interfaces, between neighboring hexamers, possibly representing the kinds of, interactions which occur in the soluble aggregates at the site of, injection. Comparison with an equivalent nonderivatized native insulin, hexamer shows that the addition of the lithocholyl group disrupts neither, the important conformational features of the insulin molecule nor its, hexamer-forming ability. Indeed, binding studies show that the affinity of, N-lithocholyl insulin for the human insulin receptor is not significantly, diminished.
DiseaseDisease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this StructureAbout this Structure
1UZ9 is a Protein complex structure of sequences from [1] with ZN, CL, CRS and UZ9 as ligands. Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Crystallographic and solution studies of N-lithocholyl insulin: a new generation of prolonged-acting human insulins., Whittingham JL, Jonassen I, Havelund S, Roberts SM, Dodson EJ, Verma CS, Wilkinson AJ, Dodson GG, Biochemistry. 2004 May 25;43(20):5987-95. PMID:15147182
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