| Metal ion controlled self-assembly of a chemically re-engineered protein drug studied by small-angle X-ray scattering. | |
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MedLine Citation:
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PMID: 22853842 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here the self-assembly of 2,2'-bipyridine conjugated monomeric insulin analogs, induced through coordination to divalent metal ions, was studied. This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II) respectively. The insulin type chosen for this study is a variant designed for a reduced tendency towards native dimer formation at physiological concentrations. A Small-Angle X-ray Scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies upon addition of Fe(II). The addition of Zn(II), on the other hand lead to the formation of small quantities of insulin hexamers for both the bipyridine-modified and the unmodified monomeric insulin. Interestingly, the location of the bipyridine-modification significantly affects the tendency to hexamer formation as compared to the unmodified insulin. Our study shows how combining a structural study and chemical design can be used to obtain molecular understanding and control of the self-assembly of a protein drug. This knowledge may eventually be employed to develop an optimized in vivo drug release profile. |
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Authors:
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Jesper Nygaard; Henrik Kofoed Munch; Peter Waaben Thulstrup; Niels Christensen; Thomas Hoeg-Jensen; Knud J Jensen; Lise Arleth |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-8-1 |
Journal Detail:
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Title: Langmuir : the ACS journal of surfaces and colloids Volume: - ISSN: 1520-5827 ISO Abbreviation: Langmuir Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-8-2 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9882736 Medline TA: Langmuir Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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