NMR probing and visualization of correlated structural fluctuations in intrinsically disordered proteins

2017 ◽  
Vol 19 (16) ◽  
pp. 10651-10656 ◽  
Author(s):  
Dennis Kurzbach ◽  
Andreas Beier ◽  
Agathe Vanas ◽  
Andrea G. Flamm ◽  
Gerald Platzer ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Statistical Analysis ◽  
Magnetic Resonance ◽  
Intrinsically Disordered Proteins ◽  
Paramagnetic Relaxation ◽  
Disordered Proteins ◽  
Correlation Matrices ◽  
Intrinsically Disordered ◽  
Nmr Data ◽  
Structural Fluctuations

A novel statistical analysis of paramagnetic relaxation enhancement (PRE) and paramagnetic relaxation interference (PRI) based nuclear magnetic resonance (NMR) data is proposed based on the computation of correlation matrices.

scholarly journals Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions

Biomolecules ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 168 ◽  
Author(s):  
Carolina Cragnell ◽  
Lasse Staby ◽  
Samuel Lenton ◽  
Birthe Kragelund ◽  
Marie Skepö
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Intrinsically Disordered Proteins ◽  
Divalent Cations ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Binding Motifs ◽  
Histatin 5 ◽  
X Ray ◽  
Intrinsically Disordered ◽  
X Ray Scattering

Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn2+ can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn2+. The process is critically dependent upon interaction between Zn2+ ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn2+ induced oligomerisation may be crucial for maintaining saliva homeostasis.

scholarly journals Detection of correlated conformational fluctuations in intrinsically disordered proteins through paramagnetic relaxation interference

2016 ◽  
Vol 18 (8) ◽  
pp. 5753-5758 ◽  
Author(s):  
D. Kurzbach ◽  
A. Vanas ◽  
A. G. Flamm ◽  
N. Tarnoczi ◽  
G. Kontaxis ◽  
...  
Keyword(s):  
Direct Observation ◽  
Intrinsically Disordered Proteins ◽  
Paramagnetic Relaxation ◽  
Disordered Proteins ◽  
Intrinsically Disordered

NMR-based paramagnetic relaxation interference (PRI) allows for direct observation of concerted motions and cooperatively folded sub-states in IDPs, via cross correlated relaxation.

scholarly journals Drug Discovery Targeting the Disorder-To-Order Transition Regions through the Conformational Diversity Mimicking and Statistical Analysis

2020 ◽  
Vol 21 (15) ◽  
pp. 5248
Author(s):  
Insung Na ◽  
Sungwoo Choi ◽  
Seung Han Son ◽  
Vladimir N. Uversky ◽  
Chul Geun Kim
Keyword(s):  
Statistical Analysis ◽  
Drug Discovery ◽  
Virtual Screening ◽  
Binding Site ◽  
Electrostatic Interaction ◽  
Intrinsically Disordered Proteins ◽  
Score Function ◽  
Order Transition ◽  
Disordered Proteins ◽  
Intrinsically Disordered

Intrinsically disordered proteins exist as highly dynamic conformational ensembles of diverse forms. However, the majority of virtual screening only focuses on proteins with defined structures. This means that computer-aided drug discovery is restricted. As a breakthrough, understanding the structural characteristics of intrinsically disordered proteins and its application can open the gate for unrestricted drug discovery. First, we segmented the target disorder-to-order transition region into a series of overlapping 20-amino-acid-long peptides. Folding prediction generated diverse conformations of these peptides. Next, we applied molecular docking, new evaluation score function, and statistical analysis. This approach successfully distinguished known compounds and their corresponding binding regions. Especially, Myc proto-oncogene protein (MYC) inhibitor 10058F4 was well distinguished from others of the chemical compound library. We also studied differences between the two Methyl-CpG-binding domain protein 2 (MBD2) inhibitors (ABA (2-amino-N-[[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]-acetamide) and APC ((R)-(3-(2-Amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester))). Both compounds bind MBD2 through electrostatic interaction behind its p66α-binding site. ABA is also able to bind p66α through electrostatic interaction behind its MBD2-binding site while APC-p66α binding was nonspecific. Therefore, structural heterogeneity mimicking of the disorder-to-order transition region at the peptide level and utilization of the new docking score function represent a useful approach that can efficiently discriminate compounds for expanded virtual screening toward intrinsically disordered proteins.

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