Creating Conformational Entropy by Increasing Interdomain Mobility in Ligand Binding Regulation: A Revisit to N-Terminal Tandem PDZ Domains of PSD-95

2009 ◽  
Vol 131 (2) ◽  
pp. 787-796 ◽  
Author(s):  
Wenning Wang ◽  
Jingwei Weng ◽  
Xu Zhang ◽  
Maili Liu ◽  
Mingjie Zhang
Keyword(s):  
Ligand Binding ◽  
Pdz Domains ◽  
Conformational Entropy

Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation

2012 ◽  
Vol 40 (2) ◽  
pp. 419-423 ◽  
Author(s):  
Mikael Akke
Keyword(s):  
Ligand Binding ◽  
Bound States ◽  
Conformational Dynamics ◽  
Nmr Relaxation ◽  
Titration Calorimetry ◽  
Conformational Entropy ◽  
Chain Order ◽  
Ligand Interactions ◽  
Galectin 3 ◽  
Relaxation Experiments

Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein–ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions.

scholarly journals Ligand binding by PDZ domains

BioFactors ◽  
2012 ◽  
Vol 38 (5) ◽  
pp. 338-348 ◽  
Author(s):  
Celestine N. Chi ◽  
Anders Bach ◽  
Kristian Strømgaard ◽  
Stefano Gianni ◽  
Per Jemth
Keyword(s):  
Ligand Binding ◽  
Pdz Domains

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 Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures

2020 ◽  
Vol 21 (21) ◽  
pp. 8348
Author(s):  
Dániel Dudola ◽  
Anett Hinsenkamp ◽  
Zoltán Gáspári
Keyword(s):  
Ligand Binding ◽  
General Feature ◽  
Allosteric Modulation ◽  
Side Chain ◽  
Ligand Specificity ◽  
Structural Rearrangements ◽  
Pdz Domains ◽  
Postsynaptic Protein ◽  
Conformational Diversity ◽  
Structural Ensembles

PDZ domains are abundant interaction hubs found in a number of different proteins and they exhibit characteristic differences in their structure and ligand specificity. Their internal dynamics have been proposed to contribute to their biological activity via changes in conformational entropy upon ligand binding and allosteric modulation. Here we investigate dynamic structural ensembles of PDZ3 of the postsynaptic protein PSD-95, calculated based on previously published backbone and side-chain S2 order parameters. We show that there are distinct but interdependent structural rearrangements in PDZ3 upon ligand binding and the presence of the intramolecular allosteric modulator helix α3. We have also compared these rearrangements in PDZ1-2 of PSD-95 and the conformational diversity of an extended set of PDZ domains available in the PDB database. We conclude that although the opening-closing rearrangement, occurring upon ligand binding, is likely a general feature for all PDZ domains, the conformer redistribution upon ligand binding along this mode is domain-dependent. Our findings suggest that the structural and functional diversity of PDZ domains is accompanied by a diversity of internal motional modes and their interdependence.

scholarly journals Synaptic MAGUK Multimer Formation Is Mediated by PDZ Domains and Promoted by Ligand Binding

2013 ◽  
Vol 20 (8) ◽  
pp. 1044-1054 ◽  
Author(s):  
Nils Rademacher ◽  
Stella-Amrei Kunde ◽  
Vera M. Kalscheuer ◽  
Sarah A. Shoichet
Keyword(s):  
Ligand Binding ◽  
Pdz Domains

scholarly journals Structural origins of protein conformational entropy

2021 ◽  
Author(s):  
José A. Caro ◽  
Kathleen G. Valentine ◽  
A. Joshua Wand
Keyword(s):  
Ligand Binding ◽  
Protein Function ◽  
Nmr Relaxation ◽  
Internal Motion ◽  
Side Chains ◽  
Conformational Entropy ◽  
Relaxation Methods ◽  
Detailed Structural Analysis ◽  
Packing Defects ◽  
Single Water Molecule

AbstractThe thermodynamics of molecular recognition by proteins is a central determinant of complex biochemistry. For over a half-century detailed cryogenic structures have provided deep insight into the energetic contributions to ligand binding by proteins1. More recently, a dynamical proxy based on NMR-relaxation methods has revealed an unexpected richness in the contributions of conformational entropy to the thermodynamics of ligand binding2,3,4,5. There remains, however, a discomforting absence of an understanding of the structural origins of fast internal motion and the conformational entropy that this motion represents. Here we report the pressure-dependence of fast internal motion within the ribonuclease barnase and its complex with the protein barstar. Distinctive clustering of the pressure sensitivity correlates with the presence of small packing defects or voids surrounding affected side chains. Prompted by this observation, we performed an analysis of the voids surrounding over 2,500 methyl-bearing side chains having experimentally determined order parameters. We find that changes in unoccupied volume as small as a single water molecule surrounding buried side chains greatly affects motion on the subnanosecond timescale. The discovered relationship begins to permit construction of a united view of the relationship between changes in the internal energy, as exposed by detailed structural analysis, and the conformational entropy, as represented by fast internal motion, in the thermodynamics of protein function.

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