کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5533146 1402103 2017 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide
ترجمه فارسی عنوان
خصوصیات توالی در اتصال وابسته به آنتروپی یک مولکول کوچک و یک پپتید اختلال
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
چکیده انگلیسی


- We show that a small molecule binds a disordered peptide in a diffuse, entropic manner.
- We observe sequence specificity in the diffuse binding, suggesting that specificity in this type of binding may be achievable.
- We demonstrate that this type of binding can alter the biophysical properties of a disordered peptide.

Approximately one-third of the human proteome is made up of proteins that are entirely disordered or that contain extended disordered regions. Although these disordered proteins are closely linked with many major diseases, their binding mechanisms with small molecules remain poorly understood, and a major concern is whether their specificity can be sufficient for drug development. Here, by studying the interaction of a small molecule and a disordered peptide from the oncogene protein c-Myc, we describe a “specific-diffuse” binding mechanism that exhibits sequence specificity despite being of entropic nature. By combining NMR spectroscopy, biophysical measurements, statistical inference, and molecular simulations, we provide a quantitative measure of such sequence specificity and compare it to the case of the interaction of urea, which is diffuse but not specific. To investigate whether this type of binding can generally modify intermolecular interactions, we show that it leads to an inhibition of the aggregation of the peptide. These results suggest that the binding mechanism that we report may create novel opportunities to discover drugs that target disordered proteins in their monomeric states in a specific manner.

Graphical Abstract279

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Biology - Volume 429, Issue 18, 1 September 2017, Pages 2772-2779
نویسندگان
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