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 Hidden electrostatic basis of dynamic allostery in a PDZ domain

2017 ◽  
Vol 114 (29) ◽  
pp. E5825-E5834 ◽  
Author(s):  
Amit Kumawat ◽  
Suman Chakrabarty
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Pdz Domain ◽  
Allosteric Modulation ◽  
Side Chain ◽  
Salt Bridges ◽  
Population Shift ◽  
Domain Protein ◽  
Dynamics Simulations

Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.

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

Side-chain flexibility in proteins upon ligand binding

2000 ◽  
Vol 39 (3) ◽  
pp. 261-268 ◽  
Author(s):  
Rafael Najmanovich ◽  
Josef Kuttner ◽  
Vladimir Sobolev ◽  
Marvin Edelman
Keyword(s):  
Ligand Binding ◽  
Side Chain ◽  
Chain Flexibility

scholarly journals Dual-mechanism estrogen receptor inhibitors expand the repertoire of anti-hormone therapy for breast cancer

2020 ◽  
Author(s):  
Jian Min ◽  
Jerome C. Nwachukwu ◽  
Sathish Srinivasan ◽  
Erumbi S. Rangarajan ◽  
Charles C. Nettles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Targeted Therapies ◽  
De Novo ◽  
Binding Pocket ◽  
Side Chain ◽  
Ligand Binding Pocket ◽  
Single Mechanism ◽  
Dual Mechanism

ABSTRACTTamoxifen and fulvestrant are currently two major approved estrogen receptor-α (ER)-targeted therapies for breast cancer, but resistance to their antagonistic actions often develops. Efforts to improve ER-targeted therapies have relied upon a single mechanism, where ligands with a single side chain on the ligand core that extends outward from the ligand binding pocket to directly displace helix (h)12 in the ER ligand-binding domain (LBD), blocking the LBD interaction with transcriptional coactivators that drive proliferation. Here, we describe ER inhibitors that block estrogen-induced proliferation through two distinct structural mechanisms by combining a side chain for direct antagonism with a bulky chemical group that causes indirect antagonism by distorting structural epitopes inside the ligand binding pocket. These dual-mechanism ER inhibitors (DMERIs) fully antagonize the proliferation of wild type ER-positive breast cancer cells and cells that have become resistant to tamoxifen and fulvestrant through activating ER mutations and de novo mechanisms such as overactive growth factor signaling. Conformational probing studies highlight marked differences that distinguish the dual mechanism inhibitors from current standard of care single-mechanism antiestrogens, and crystallographic analyses reveal that they disrupt the positioning of h11 and h12 in multiple ways. Combining two chemical targeting approaches into a single ligand thus provides a flexible platform for next generation ER-targeted therapies.

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