scholarly journals Interdependence of intra- and inter-domain motions in the PSD-95 PDZ12 tandem

2019 ◽  
Author(s):  
Bertalan Kovács ◽  
Nóra Zajácz-Epresi ◽  
Zoltán Gáspári
Keyword(s):  
Ligand Binding ◽  
Structural Changes ◽  
Regulatory Region ◽  
Peptide Ligand ◽  
Pdz Domains ◽  
Specific Domain ◽  
Interatomic Distances ◽  
Conformational Ensembles ◽  
Domain Motions ◽  
Partner Proteins

AbstractPSD-95 is the most abundant scaffold protein in the postsynaptic density of neurons. Its two N-terminal PDZ domains form an autonomous structural unit and their interdomain orientation and dynamics was shown to be dependent on binding to various partner proteins. To understand the mechanistic details of the effect of ligand binding on interdomain structure and dynamics, we generated conformational ensembles using experimentally determined NOE interatomic distances and S2order parameters, available from the literature. In our approach no explicit restraints between the two domains were used and their fast dynamics was also treated independently. We found that intradomain structural changes induced by ligand binding have a profound effect on the interfaces where interdomain contacts can be formed, modulating the probability of the occurrence of specific domain-domain orientations. Our results suggest that the β2-β3 loop in the PDZ domains is a key regulatory region that, through interacting with the upstream residues of the C-terminal peptide ligand, influences both intradomain motions and supramodular rearrangement.

scholarly journals D3PM: A Comprehensive Database for Protein Motions Ranging from Residue to Domain

2020 ◽  
Author(s):  
Cheng Peng ◽  
Xinben Zhang ◽  
Zhijian Xu ◽  
Zhaoqiang Chen ◽  
Yanqing Yang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Small Scale ◽  
Motion Patterns ◽  
Protein Motions ◽  
Protein Functions ◽  
Binding Pockets ◽  
Local Residue ◽  
Domain Motions

Abstract Background: Knowledge of protein motions is significant to understand its functions. The currently available databases for protein motions, in general, are focused on overall domain motions, which pay little attention to local residue motions. Albeit with relatively small scale, the local residue motions may play crucial roles in protein functions and its binding with ligand, in particular for those residues within binding pockets. Results: A comprehensive protein motion database (D3PM) was constructed in this study to facilitate the analysis of protein motions. The D3PM has the motion information ranging from the overall structural changes of macromolecule to the local flip motion of the residues in ligand binding site. Currently, the D3PM has 5,339 entries of overall motions and 2,319 entries of pocket residues’ motions. The motion patterns in the database are classified into 4 types of overall structural change and 5 types of pocket residues’ shift. Impressively, it was found that less than 15% of the protein pairs have obvious overall conformational adaptations induced by ligand binding, while more than 50% of the protein pairs have significant structural changes in the ligand binding sites, indicating that ligand-induced conformational changes are drastic whereas they are mostly confined around the ligand. By the analysis of pocket residues’ preference, we classified amino acids into “pocketphilic” and “pocketphobic” residues, which is helpful to pocket prediction and ligand design.Conclusion: D3PM is a comprehenssive database about protein motions ranging from residue to domain, which should be useful for exploring diverse protein motions and for understanding protein functions. The database is freely available on www.d3pharma.com/D3PM/index.php.

scholarly journals A graph-based algorithm for detecting rigid domains in protein structures

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Truong Khanh Linh Dang ◽  
Thach Nguyen ◽  
Michael Habeck ◽  
Mehmet Gültas ◽  
Stephan Waack
Keyword(s):  
Structural Changes ◽  
Viterbi Algorithm ◽  
Structural Information ◽  
Line Graph ◽  
Clustering Algorithms ◽  
Protein Structures ◽  
Alternative Methods ◽  
Structural Transitions ◽  
Tuning Parameters ◽  
Conformational Ensembles

Abstract Background Conformational transitions are implicated in the biological function of many proteins. Structural changes in proteins can be described approximately as the relative movement of rigid domains against each other. Despite previous efforts, there is a need to develop new domain segmentation algorithms that are capable of analysing the entire structure database efficiently and do not require the choice of protein-dependent tuning parameters such as the number of rigid domains. Results We develop a graph-based method for detecting rigid domains in proteins. Structural information from multiple conformational states is represented by a graph whose nodes correspond to amino acids. Graph clustering algorithms allow us to reduce the graph and run the Viterbi algorithm on the associated line graph to obtain a segmentation of the input structures into rigid domains. In contrast to many alternative methods, our approach does not require knowledge about the number of rigid domains. Moreover, we identified default values for the algorithmic parameters that are suitable for a large number of conformational ensembles. We test our algorithm on examples from the DynDom database and illustrate our method on various challenging systems whose structural transitions have been studied extensively. Conclusions The results strongly suggest that our graph-based algorithm forms a novel framework to characterize structural transitions in proteins via detecting their rigid domains. The web server is available at http://azifi.tz.agrar.uni-goettingen.de/webservice/.

scholarly journals Interbase-FRET binding assay for pre-microRNAs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mattias Bood ◽  
Anna Wypijewska del Nogal ◽  
Jesper R. Nilsson ◽  
Fredrik Edfeldt ◽  
Anders Dahlén ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Drug Targets ◽  
Structural Changes ◽  
Small Sample Size ◽  
Resonance Energy ◽  
Small Sample ◽  
Titration Calorimetry ◽  
Drug Candidate ◽  
Binding Studies ◽  
Aberrant Expression

AbstractThe aberrant expression of microRNAs (miRs) has been linked to several human diseases. A promising approach for targeting these anomalies is the use of small-molecule inhibitors of miR biogenesis. These inhibitors have the potential to (i) dissect miR mechanisms of action, (ii) discover new drug targets, and (iii) function as new therapeutic agents. Here, we designed Förster resonance energy transfer (FRET)-labeled oligoribonucleotides of the precursor of the oncogenic miR-21 (pre-miR-21) and used them together with a set of aminoglycosides to develop an interbase-FRET assay to detect ligand binding to pre-miRs. Our interbase-FRET assay accurately reports structural changes of the RNA oligonucleotide induced by ligand binding. We demonstrate its application in a rapid, qualitative drug candidate screen by assessing the relative binding affinity between 12 aminoglycoside antibiotics and pre-miR-21. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were used to validate our new FRET method, and the accuracy of our FRET assay was shown to be similar to the established techniques. With its advantages over SPR and ITC owing to its high sensitivity, small sample size, straightforward technique and the possibility for high-throughput expansion, we envision that our solution-based method can be applied in pre-miRNA–target binding studies.

Investigations of Actinide Metals and Compounds under Pressure Provide Important Insights into Bonding and Chemistry

2003 ◽  
Vol 802 ◽  
Author(s):  
R. G. Haire ◽  
S. Heathman ◽  
T. Le Bihan ◽  
A. Lindbaum ◽  
M. Iridi
Keyword(s):  
Structural Changes ◽  
Chemical Properties ◽  
X Ray Diffraction ◽  
Interatomic Distances ◽  
X Ray ◽  
Effect Of Pressure ◽  
Electronic Configurations ◽  
5F Electrons ◽  
Actinide Series ◽  
Alloys And Compounds

ABSTRACTOne effect of pressure on elements and compounds is to decease their interatomic distances, which can bring about dramatic perturbations in their electronic nature and bonding, which can be reflected in changes in physical and/or chemical properties. One important issue in the actinide series of elements is the effect of pressure on the 5f-electrons. We have probed changes in electronic behavior with pressure by monitoring structure by X-ray diffraction, and have studied several actinide metals and compounds from thorium through einsteinium. These studies have employed angle dispersive diffraction using synchrotron radiation, and energy dispersive techniques via conventional X-ray sources. The 5f-electrons of actinide metals and their alloys are often affected significantly by pressure, while with compounds, the structural changes are often not linked to the involvement of 5 f-electron. We shall present some of our more recent findings from studies of selected actinide metals, alloys and compounds under pressure. A discussion of the results in terms of the changes in electronic configurations and bonding with regard to the element's position in the series is also addressed.

Mechanochemical Activation of Class-B G-Protein-Coupled Receptor upon Peptide–Ligand Binding

Nano Letters ◽  
2020 ◽  
Vol 20 (7) ◽  
pp. 5575-5582 ◽  
Author(s):  
Cristina Lo Giudice ◽  
Haonan Zhang ◽  
Beili Wu ◽  
David Alsteens
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Mechanochemical Activation ◽  
Peptide Ligand ◽  
G Protein Coupled Receptor ◽  
Class B ◽  
G Protein Coupled

scholarly journals Sensing the allosteric force

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Olga Bozovic ◽  
Brankica Jankovic ◽  
Peter Hamm
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Chemical Reactions ◽  
Peptide Ligand ◽  
Allosteric Site ◽  
Small Peptide ◽  
Changing Environment ◽  
Allosteric Communication ◽  
Signalling Cascades ◽  
Living Organisms

AbstractAllosteric regulation is an innate control in most metabolic and signalling cascades that enables living organisms to adapt to the changing environment by tuning the affinity and regulating the activity of target proteins. For a microscopic understanding of this process, a protein system has been designed in such a way that allosteric communication between the binding and allosteric site can be observed in both directions. To that end, an azobenzene-derived photoswitch has been linked to the α3-helix of the PDZ3 domain, arguably the smallest allosteric protein with a clearly identifiable binding and allosteric site. Photo-induced trans-to-cis isomerisation of the photoswitch increases the binding affinity of a small peptide ligand to the protein up to 120-fold, depending on temperature. At the same time, ligand binding speeds up the thermal cis-to-trans back-isomerisation rate of the photoswitch. Based on the energetics of the four states of the system (cis vs trans and ligand-bound vs free), the concept of an allosteric force is introduced, which can be used to drive chemical reactions.

Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding

2010 ◽  
Vol 391 (1) ◽  
Author(s):  
Renu Batra-Safferling ◽  
Joachim Granzin ◽  
Susanne Mödder ◽  
Silke Hoffmann ◽  
Dieter Willbold
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Protein Interactions ◽  
Intracellular Signaling ◽  
Sh3 Domain ◽  
Peptide Ligand ◽  
Type I ◽  
Phosphatidylinositol 3 Kinase ◽  
Anchor Residue ◽  
Phosphatidylinositol 3

Abstract Src homology 3 (SH3) domains are mediators of protein-protein interactions. They comprise approximately 60 amino acid residues and are found in many intracellular signaling proteins. Here, we present the crystal structure of the SH3 domain from phosphatidylinositol 3-kinase (PI3K) in complex with the 12-residue proline-rich peptide PD1R (HSKRPLPPLPSL). The crystal structure of the PI3K SH3-PD1R complex at a resolution of 1.7 Å reveals type I ligand orientation of the bound peptide with an extended conformation where the central portion forms a left-handed type II polyproline (PPII) helix. The overall structure of the SH3 domain shows minimal changes on ligand binding. In addition, we also attempted crystallization with another peptide ligand (PD1) where the residue at anchor position P-3 is a tyrosine. The crystals obtained did not contain the PD1 ligand; instead, the ligand binding site is partially occupied by residues Arg18 and Trp55 from the symmetry-related PI3K SH3 molecule. Considering these crystal structures of PI3K SH3 together with published reports, we provide a comparative analysis of protein-ligand interactions that has helped us identify the individual residues which play an important role in defining target specificity.

Growth-regulatory Human Galectin-1: Crystallographic Characterisation of the Structural Changes Induced by Single-site Mutations and their Impact on the Thermodynamics of Ligand Binding

2004 ◽  
Vol 343 (4) ◽  
pp. 957-970 ◽  
Author(s):  
María F. López-Lucendo ◽  
Dolores Solís ◽  
Sabine André ◽  
Jun Hirabayashi ◽  
Ken-ichi Kasai ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Changes ◽  
Single Site
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