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X-ray crystallographic and hydrogen deuterium exchange studies confirm alternate kinetic models for homolog insulin monomers

Ayan, Esra ; Türk, Miray ; Tatlı, Özge LU ; Bostan, Sevginur ; Telek, Elek ; Dingiloğlu, Baran ; Doğan, B. Züleyha ; Alp, Muhammed Ikbal ; Katı, Ahmet and Dinler-Doğanay, Gizem , et al. (2025) In PLoS ONE 20(4 APRIL).
Abstract

Despite the crucial role of various insulin analogs in achieving satisfactory glycemic control, a comprehensive understanding of their in-solution dynamic mechanisms still holds the potential to further optimize rapid insulin analogs, thus significantly improving the well-being of individuals with Type 1 Diabetes. Here, we employed hydrogen-deuterium exchange mass spectrometry to decipher the molecular dynamics of newly modified and functional insulin analog. A comparative analysis of H/D dynamics demonstrated that the modified insulin exchanges deuterium atoms faster and more extensively than the intact insulin aspart. Additionally, we present new insights derived from our 2.5 Å resolution X-ray crystal structure of modified hexamer... (More)

Despite the crucial role of various insulin analogs in achieving satisfactory glycemic control, a comprehensive understanding of their in-solution dynamic mechanisms still holds the potential to further optimize rapid insulin analogs, thus significantly improving the well-being of individuals with Type 1 Diabetes. Here, we employed hydrogen-deuterium exchange mass spectrometry to decipher the molecular dynamics of newly modified and functional insulin analog. A comparative analysis of H/D dynamics demonstrated that the modified insulin exchanges deuterium atoms faster and more extensively than the intact insulin aspart. Additionally, we present new insights derived from our 2.5 Å resolution X-ray crystal structure of modified hexamer insulin analog at ambient temperature. Furthermore, we obtained a distinctive side-chain conformation of the Asn3 residue on the B chain (AsnB3) by operating a comparative analysis with a previously available cryogenic rapid-acting insulin structure (PDB_ID: 4GBN). The experimental conclusions have demonstrated compatibility with modified insulin’s distinct cellular activity, comparably to aspart. Additionally, the hybrid structural approach combined with computational analysis employed in this study provides novel insight into the structural dynamics of newly modified and functional insulin vs insulin aspart monomeric entities. It allows further molecular understanding of intermolecular interrelations driving dissociation kinetics and, therefore, a fast action mechanism.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
20
issue
4 APRIL
article number
e0319282
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:40257998
  • scopus:105003691828
ISSN
1932-6203
DOI
10.1371/journal.pone.0319282
language
English
LU publication?
yes
id
399ee7f8-b3fd-4a53-ab6f-95c3f913a7dd
date added to LUP
2025-08-13 11:33:56
date last changed
2025-09-24 19:46:34
@article{399ee7f8-b3fd-4a53-ab6f-95c3f913a7dd,
  abstract     = {{<p>Despite the crucial role of various insulin analogs in achieving satisfactory glycemic control, a comprehensive understanding of their in-solution dynamic mechanisms still holds the potential to further optimize rapid insulin analogs, thus significantly improving the well-being of individuals with Type 1 Diabetes. Here, we employed hydrogen-deuterium exchange mass spectrometry to decipher the molecular dynamics of newly modified and functional insulin analog. A comparative analysis of H/D dynamics demonstrated that the modified insulin exchanges deuterium atoms faster and more extensively than the intact insulin aspart. Additionally, we present new insights derived from our 2.5 Å resolution X-ray crystal structure of modified hexamer insulin analog at ambient temperature. Furthermore, we obtained a distinctive side-chain conformation of the Asn3 residue on the B chain (AsnB3) by operating a comparative analysis with a previously available cryogenic rapid-acting insulin structure (PDB_ID: 4GBN). The experimental conclusions have demonstrated compatibility with modified insulin’s distinct cellular activity, comparably to aspart. Additionally, the hybrid structural approach combined with computational analysis employed in this study provides novel insight into the structural dynamics of newly modified and functional insulin vs insulin aspart monomeric entities. It allows further molecular understanding of intermolecular interrelations driving dissociation kinetics and, therefore, a fast action mechanism.</p>}},
  author       = {{Ayan, Esra and Türk, Miray and Tatlı, Özge and Bostan, Sevginur and Telek, Elek and Dingiloğlu, Baran and Doğan, B. Züleyha and Alp, Muhammed Ikbal and Katı, Ahmet and Dinler-Doğanay, Gizem and Demirci, Hasan}},
  issn         = {{1932-6203}},
  language     = {{eng}},
  number       = {{4 APRIL}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{X-ray crystallographic and hydrogen deuterium exchange studies confirm alternate kinetic models for homolog insulin monomers}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0319282}},
  doi          = {{10.1371/journal.pone.0319282}},
  volume       = {{20}},
  year         = {{2025}},
}