Journal
BIOCHEMISTRY
Volume 52, Issue 2, Pages 282-294Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi3008615
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Funding
- Drug Research Academy at the Faculty of Health and Medical Sciences, University of Copenhagen
- Novo Nordisk A/S
- Carlsberg Foundation
- Danish Council for Independent Research, Medical Sciences
- DANSCATT
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Lys(B29)(N-epsilon omega-carboxyheptadecanoyl) des(B30) human insulin is an insulin analogue belonging to a class of analogues designed to form soluble depots in subcutis by self-association, aiming at a protracted action. On the basis of small angle X-ray scattering (SAXS) supplemented by a range of biophysical and structural methods (field flow fractionation, dynamic and multiangle light scattering, circular dichroism, size exclusion chromatography, and crystallography), we propose a mechanism for the self-association expected to occur upon subcutaneous injection of this insulin analogue. SAXS data provide evidence of the in solution structure of the self-associated oligomer, which is a long straight rod composed of tense state insulin hexamers (T-6-hexamers) as the smallest repeating unit. The smallest oligomer building block in the process is a T6T6-dihexamer. This tense dihexamer is formed by the allosteric change of the initial equilibrium between a proposed relaxed state R-6-hexamer and an R3T3T3R3-dihexamer. The allosteric change from relaxed to tense is triggered by removal of phenol, mimicking subcutaneous injection. The data hence provide the first unequivocal evidence of the mechanism of self-association for this type of insulin analogue.
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