How to distinguish ligand-binding mechanisms: an example of conformational selection disguised as an induced fit

2019 ◽  
pp. 1-16
Author(s):  
Santiago Enrique Faraj ◽  
Rolando Carlos Rossi ◽  
Mónica Raquel Montes
Keyword(s):  
Ligand Binding ◽  
Induced Fit ◽  
Conformational Selection ◽  
Binding Mechanisms

scholarly journals A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein

2011 ◽  
Vol 7 (5) ◽  
pp. e1002054 ◽  
Author(s):  
Daniel-Adriano Silva ◽  
Gregory R. Bowman ◽  
Alejandro Sosa-Peinado ◽  
Xuhui Huang
Keyword(s):  
Ligand Binding ◽  
Induced Fit ◽  
Conformational Selection

scholarly journals Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding

2015 ◽  
Vol 112 (31) ◽  
pp. 9614-9619 ◽  
Author(s):  
Munehito Arai ◽  
Kenji Sugase ◽  
H. Jane Dyson ◽  
Peter E. Wright
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Terminal Region ◽  
Relaxation Dispersion ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Induced Fit ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Factor C ◽  
Binding Mechanisms

Intrinsically disordered proteins (IDPs) frequently function in protein interaction networks that regulate crucial cellular signaling pathways. Many IDPs undergo transitions from disordered conformational ensembles to folded structures upon binding to their cellular targets. Several possible binding mechanisms for coupled folding and binding have been identified: folding of the IDP after association with the target (“induced fit”), or binding of a prefolded state in the conformational ensemble of the IDP to the target protein (“conformational selection”), or some combination of these two extremes. The interaction of the intrinsically disordered phosphorylated kinase-inducible domain (pKID) of the cAMP-response element binding (CREB) protein with the KIX domain of a general transcriptional coactivator CREB-binding protein (CBP) provides an example of the induced-fit mechanism. Here we show by NMR relaxation dispersion experiments that a different intrinsically disordered ligand, the transactivation domain of the transcription factor c-Myb, interacts with KIX at the same site as pKID but via a different binding mechanism that involves elements of conformational selection and induced fit. In contrast to pKID, the c-Myb activation domain has a strong propensity for spontaneous helix formation in its N-terminal region, which binds to KIX in a predominantly folded conformation. The C-terminal region of c-Myb exhibits a much smaller helical propensity and likely folds via an induced-fit process after binding to KIX. We propose that the intrinsic secondary structure propensities of pKID and c-Myb determine their binding mechanisms, consistent with their functions as inducible and constitutive transcriptional activators.

scholarly journals Resolving Three-State Ligand-Binding Mechanisms by Isothermal Titration Calorimetry: A Simulation Study

2017 ◽  
Author(s):  
Evgenii L. Kovrigin
Keyword(s):  
Ligand Binding ◽  
Isothermal Titration Calorimetry ◽  
Simulation Study ◽  
Titration Calorimetry ◽  
Induced Fit ◽  
State Process ◽  
Binding Mechanisms

ABSTRACTIn this paper, I theoretically analyzed ITC profiles for three-state equilibria involving ligand binding coupled to isomerization or dimerization transitions. Simulations demonstrate that the mechanisms where the free or ligand-bound protein undergoes dimerization (such that the ligand cannot bind to or dissociate from the dimer) produce very distinctive titration profiles. In contrast, profiles of the pre-existing equilibrium or induced-fit models cannot be distinguished from a simple two-state process, requiring data from additional techniques to positively identify these mechanisms.

scholarly journals Conformational selection vs. induced fit: insights into the binding mechanisms of p38α MAP Kinase inhibitors

2020 ◽  
Vol 56 (62) ◽  
pp. 8818-8821
Author(s):  
Patrick Roser ◽  
Jörn Weisner ◽  
Juliane Stehle ◽  
Daniel Rauh ◽  
Malte Drescher
Keyword(s):  
Map Kinase ◽  
Direct Evidence ◽  
Kinase Inhibitors ◽  
Induced Fit ◽  
Conformational Selection ◽  
Ligand Type ◽  
Distance Restraints ◽  
Selection Mechanisms ◽  
P38α Map Kinase ◽  
Binding Mechanisms

Multilateration using EPR distance restraints shows direct evidence of both induced-fit and conformational selection mechanisms of p38α depending on the ligand type.

Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection

2018 ◽  
Vol 20 (36) ◽  
pp. 23222-23232 ◽  
Author(s):  
Yang Zhou ◽  
Muzammal Hussain ◽  
Guanglin Kuang ◽  
Jiancun Zhang ◽  
Yaoquan Tu
Keyword(s):  
Ligand Binding ◽  
Peptide Binding ◽  
Atomistic Simulations ◽  
Induced Fit ◽  
Conformational Selection

Atomistic simulations of the ATAD2-bromodomain disclose a role of induced fit and conformational selection upon ligand and peptide binding.

Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

2019 ◽  
Author(s):  
Duy Phuoc Tran ◽  
Akio Kitao
Keyword(s):  
Free Energy ◽  
Transcriptional Activation ◽  
Binding Free Energy ◽  
Energy Structure ◽  
Induced Fit ◽  
Hydrogen Bond Formation ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region ◽  
Dissociation Mechanisms

<p>We investigate association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor repressor protein p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard MD, and Markov state model, we are successful in obtaining the lowest free energy structure of MDM2/TAD-p53 complex as the structure very close to that in crystal without prior knowledge. This method also reproduces the experimentally measured standard binding free energy, and association and dissociation rate constants solely with the accumulated MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation occurs in the order of a second. Although there exist a few complex intermediates with similar free energies, TAD-p53 first binds MDM2 as the second lowest free energy intermediate dominantly (> 90% in flux), taking a form similar to one of the intermediate structures in its monomeric state. The mechanism of this step has a feature of conformational selection. In the second step, dehydration of the interface, formation of π-π stackings of the side-chains, and main-chain relaxation/hydrogen bond formation to complete α-helix take place, showing features of induced fit. In addition, dehydration (dewetting) is a key process for the final relaxation around the complex interface. These results demonstrate a more fine-grained view of the IDR association/dissociation beyond classical views of protein conformational change upon binding.</p>

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