Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding

2021 ◽  
Author(s):  
Rajitha Rajeshwar T ◽  
Moumita Saharay ◽  
Jeremy C. Smith ◽  
Marimuthu Krishnan
Keyword(s):  
Ligand Binding ◽  
Side Chain ◽  
Correlated Response ◽  
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 Characterization of the dynamics and the conformational entropy in the binding between TAZ1 and CTAD-HIF-1α

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ida Nyqvist ◽  
Jakob Dogan
Keyword(s):  
Entropy Change ◽  
Side Chain ◽  
Transactivation Domain ◽  
Creb Binding Protein ◽  
Conformational Entropy ◽  
Internal Motions ◽  
Relaxation Measurements ◽  
Nanosecond Dynamics

Abstract The interaction between the C-terminal transactivation domain of HIF-1α (CTAD-HIF-1α) and the transcriptional adapter zinc binding 1 (TAZ1) domain of CREB binding protein participate in the initiation of gene transcription during hypoxia. Unbound CTAD-HIF-1α is disordered but undergoes a disorder-to-order transition upon binding to TAZ1. We have here performed NMR side chain and backbone relaxation studies on TAZ1 and side chain relaxation measurements on CTAD-HIF-1α in order to investigate the role of picosecond to nanosecond dynamics. We find that the internal motions are significantly affected upon binding, both on the side chain and the backbone level. The dynamic response corresponds to a conformational entropy change that contributes substantially to the binding thermodynamics for both binding partners. Furthermore, the conformational entropy change for the well-folded TAZ1 varies upon binding to different IDP targets. We further identify a cluster consisting of side chains in bound TAZ1 and CTAD-HIF-1α that experience extensive dynamics and are part of the binding region that involves the N-terminal end of the LPQL motif in CTAD-HIF-1α; a feature that might have an important role in the termination of the hypoxic response.

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 Side-chain conformational entropy at protein-protein interfaces

2009 ◽  
Vol 11 (12) ◽  
pp. 2860-2870 ◽  
Author(s):  
Christian Cole ◽  
Jim Warwicker
Keyword(s):  
Side Chain ◽  
Conformational Entropy ◽  
Protein Interfaces

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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