Ein Beitrag zur Symptomatologie und Pathogenese der Dystrophia myotonica

Becher, Fritz

doi:10.1007/bf00217813

Cited by 7 publications

(1 citation statement)

References 2 publications

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“…Their data revealed that there is a strong pH-dependence to the unusual kinetic behavior observed, and it was suggested from p K a studies that this property could be due to protonation/deprotonation of the N-terminus. Later studies on GLP‑1 at other pH values and on a C-terminally amidated form of GLP‑1 showed that net charge is likely a factor in determining whether off-pathway species are formed . In addition, more recent studies have shown that the stable, off-pathway oligomer formed under some conditions can inhibit aggregation .…”

Section: Introductionmentioning

confidence: 99%

Energy Landscapes and Structural Ensembles of Glucagon-like Peptide-1 Monomers

Keith,

Brichtová,

Barber

et al. 2024

J. Phys. Chem. B

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While GLP-1 and its analogues are important pharmaceutical agents in the treatment of type 2 diabetes and obesity, their susceptibility to aggregate into amyloid fibrils poses a significant safety issue. Many factors may contribute to the aggregation propensity, including pH. While it is known that the monomeric structure of GLP-1 has a strong impact on primary nucleation, probing its diverse structural ensemble is challenging. Here, we investigated the monomer structural ensembles at pH 3, 4, and 7.5 using state-of-the-art computational methods in combination with experimental data. We found significant stabilization of β-strand structures and destabilization of helical structures at lower pH, correlating with observed aggregation lag times, which are lower under these conditions. We further identified helical defects at pH 4, which led to the fastest observed aggregation, in agreement with our far-UV circular dichroism data. The detailed atomistic structures that result from the computational studies help to rationalize the experimental results on the aggregation propensity of GLP-1. This work provides a new insight into the pH-dependence of monomeric structural ensembles of GLP-1 and connects them to experimental observations.

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Section: Introductionmentioning

confidence: 99%