Solution structures of long-acting insulin analogues and their complexes with albumin

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Solution structures of long-acting insulin analogues and their complexes with albumin. / Ryberg, Line A.; Sønderby, Pernille; Barrientos, Fabian; Bukrinski, Jens T.; Peters, Günther H.J.; Harris, Pernille.

In: Acta crystallographica Section D: Structural biology , Vol. 75, No. 3, 03.2019, p. 272-282.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ryberg, LA, Sønderby, P, Barrientos, F, Bukrinski, JT, Peters, GHJ & Harris, P 2019, 'Solution structures of long-acting insulin analogues and their complexes with albumin', Acta crystallographica Section D: Structural biology , vol. 75, no. 3, pp. 272-282. https://doi.org/10.1107/S2059798318017552

APA

Ryberg, L. A., Sønderby, P., Barrientos, F., Bukrinski, J. T., Peters, G. H. J., & Harris, P. (2019). Solution structures of long-acting insulin analogues and their complexes with albumin. Acta crystallographica Section D: Structural biology , 75(3), 272-282. https://doi.org/10.1107/S2059798318017552

Vancouver

Ryberg LA, Sønderby P, Barrientos F, Bukrinski JT, Peters GHJ, Harris P. Solution structures of long-acting insulin analogues and their complexes with albumin. Acta crystallographica Section D: Structural biology . 2019 Mar;75(3):272-282. https://doi.org/10.1107/S2059798318017552

Author

Ryberg, Line A. ; Sønderby, Pernille ; Barrientos, Fabian ; Bukrinski, Jens T. ; Peters, Günther H.J. ; Harris, Pernille. / Solution structures of long-acting insulin analogues and their complexes with albumin. In: Acta crystallographica Section D: Structural biology . 2019 ; Vol. 75, No. 3. pp. 272-282.

Bibtex

@article{adb085ba87bf41eaaaffb73e13ff6a6f,
title = "Solution structures of long-acting insulin analogues and their complexes with albumin",
abstract = "The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of self-association and association with human serum albumin (albumin). The self-association and association with albumin of two insulin analogues, insulin detemir and insulin degludec, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) in phenolic buffers. Detemir shows concentration-dependent self-association, with an equilibrium between hexamer, dihexamer, trihexamer and larger species, while degludec appears as a dihexamer independent of concentration. The solution structure of the detemir trihexamer has a bent shape. The stoichiometry of the association with albumin was studied using DLS. For albumin–detemir the molar stoichiometry was determined to be 1:6 (albumin:detemir ratio) and for albumin–degludec it was between 1:6 and 1:12 (albumin:degludec ratio). Batch SAXS measurements of a 1:6 albumin:detemir concentration series revealed a concentration dependence of complex formation. The data allowed the modelling of a complex between albumin and a detemir hexamer and a complex consisting of two albumins binding to opposite ends of a detemir dihexamer. Measurements of size-exclusion chromatography coupled to SAXS revealed a complex between a degludec dihexamer and albumin. Based on the results, equilibria for the albumin–detemir and albumin–degludec mixtures are proposed.",
keywords = "albumin, insulin analogues, insulin degludec, insulin detemir, protein complexes, rigid-body modelling, SAXS",
author = "Ryberg, {Line A.} and Pernille S{\o}nderby and Fabian Barrientos and Bukrinski, {Jens T.} and Peters, {G{\"u}nther H.J.} and Pernille Harris",
year = "2019",
month = mar,
doi = "10.1107/S2059798318017552",
language = "English",
volume = "75",
pages = "272--282",
journal = "Acta Crystallographica Section D: Structural Biology",
issn = "2059-7983",
publisher = "International Union of Crystallography",
number = "3",

}

RIS

TY - JOUR

T1 - Solution structures of long-acting insulin analogues and their complexes with albumin

AU - Ryberg, Line A.

AU - Sønderby, Pernille

AU - Barrientos, Fabian

AU - Bukrinski, Jens T.

AU - Peters, Günther H.J.

AU - Harris, Pernille

PY - 2019/3

Y1 - 2019/3

N2 - The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of self-association and association with human serum albumin (albumin). The self-association and association with albumin of two insulin analogues, insulin detemir and insulin degludec, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) in phenolic buffers. Detemir shows concentration-dependent self-association, with an equilibrium between hexamer, dihexamer, trihexamer and larger species, while degludec appears as a dihexamer independent of concentration. The solution structure of the detemir trihexamer has a bent shape. The stoichiometry of the association with albumin was studied using DLS. For albumin–detemir the molar stoichiometry was determined to be 1:6 (albumin:detemir ratio) and for albumin–degludec it was between 1:6 and 1:12 (albumin:degludec ratio). Batch SAXS measurements of a 1:6 albumin:detemir concentration series revealed a concentration dependence of complex formation. The data allowed the modelling of a complex between albumin and a detemir hexamer and a complex consisting of two albumins binding to opposite ends of a detemir dihexamer. Measurements of size-exclusion chromatography coupled to SAXS revealed a complex between a degludec dihexamer and albumin. Based on the results, equilibria for the albumin–detemir and albumin–degludec mixtures are proposed.

AB - The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of self-association and association with human serum albumin (albumin). The self-association and association with albumin of two insulin analogues, insulin detemir and insulin degludec, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) in phenolic buffers. Detemir shows concentration-dependent self-association, with an equilibrium between hexamer, dihexamer, trihexamer and larger species, while degludec appears as a dihexamer independent of concentration. The solution structure of the detemir trihexamer has a bent shape. The stoichiometry of the association with albumin was studied using DLS. For albumin–detemir the molar stoichiometry was determined to be 1:6 (albumin:detemir ratio) and for albumin–degludec it was between 1:6 and 1:12 (albumin:degludec ratio). Batch SAXS measurements of a 1:6 albumin:detemir concentration series revealed a concentration dependence of complex formation. The data allowed the modelling of a complex between albumin and a detemir hexamer and a complex consisting of two albumins binding to opposite ends of a detemir dihexamer. Measurements of size-exclusion chromatography coupled to SAXS revealed a complex between a degludec dihexamer and albumin. Based on the results, equilibria for the albumin–detemir and albumin–degludec mixtures are proposed.

KW - albumin

KW - insulin analogues

KW - insulin degludec

KW - insulin detemir

KW - protein complexes

KW - rigid-body modelling

KW - SAXS

U2 - 10.1107/S2059798318017552

DO - 10.1107/S2059798318017552

M3 - Journal article

C2 - 30950398

AN - SCOPUS:85064004120

VL - 75

SP - 272

EP - 282

JO - Acta Crystallographica Section D: Structural Biology

JF - Acta Crystallographica Section D: Structural Biology

SN - 2059-7983

IS - 3

ER -

ID: 249865308