24 papers · ranked by Valyu relevance
Mustafa Korkutata, Lokesh Agrawal, Michael Lazarus, Francisco Ciruela
'Francisco Ciruela'] The therapeutic potential of targeting adenosine A2A receptors (A2ARs) is immense due to their broad expression in the body and central nervous system. The role of A2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been…
Jan Jakubík, Alena Randáková, Nikolai Chetverikov, Esam E. El-Fakahany + 1 more
'Esam E. El-Fakahany' 'Vladimír Doležal'] Proper determination of agonist efficacy is indispensable in the evaluation of agonist selectivity and bias to activation of specific signalling pathways. The operational model (OM) of pharmacological agonism is a useful means for achieving this goal. Allosteric ligands bind to…
Jan Jakubík, Esam E. El-Fakahany
An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of gallamine as the…
Xin Liu, Yunxiang Sun, Yulong Xia, Huaqiong Li + 2 more
Allosteric modulation has emerged as a powerful strategy for achieving superior selectivity and safety in drug discovery and protein function regulation. Unlike highly conserved orthosteric sites, allosteric pockets are structurally diverse and less evolutionarily constrained, making them particularly suitable for…
R. C. Eccleston, N. Furnham
Allosteric modulators as therapeutics offer many advantages over orthosteric modulators, including improved selectivity and tunability. However, identifying and characterising allosteric sites remains a major challenge both experimentally and computationally. Accurate prediction of allosteric binding sites is critical…
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun + 3 more
'Zhenhua Shao'] G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathways…
Enrico Guarnera, Igor N. Berezovsky
On the basis of the perturbation nature of allosteric communication, a computational framework is proposed for estimating the energetics of signaling caused by the ligand binding and mutations. The perturbations are modelled as alterations of the strenght of interactions in the protein contact network in the binding…
Marijke Brams, Cedric Govaerts, Kumiko Kambara, Kerry Price + 9 more
Pentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of…
Jan Jakubik, Esam E. El-Fakahany
Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical…
Yongchang Chang, Yao Huang, Paul Whiteaker
The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls…
Authors not listed
Allosteric modulators offers a promising approach for targeting receptor function in pathological contexts. Although numerous orthosteric ligands have been developed, the discovery of allosteric inhibitors remains limited, hindered by challenges with identifying modulators and the perceived lower druggability of…
Nan Wu, Léonie Strömich, Sophia N. Yaliraki
Allostery is a pervasive mechanism which regulates the activity of proteins in living systems through binding of a molecule at a distant site from the orthosteric site of the protein. The universality of allosteric regulation complemented by the benefits of highly specific, potentially non-toxic and protein activity…
Hung N. Do, Jinan Wang, Yinglong Miao
G-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and represent primary targets of ∼1/3 of currently marketed drugs. Allosteric modulators have emerged as more selective drug candidates compared with orthosteric agonists and antagonists. However, many X-ray and cryo-EM…
Wessel A.C. Burger, Christopher J. Draper-Joyce, Celine Valant, Arthur Christopoulos + 1 more
The activation of a G protein-coupled receptor (GPCR) leads to the formation of a ternary complex between agonist, receptor, and G protein that is characterised by high-affinity binding. Allosteric modulators bind to a distinct binding site from the orthosteric agonist and can modulate both the affinity and the…
Gemma Fisher, Marina Corbella, Magnus S. Alphey, John Nicholson + 3 more
ATP phosphoribosyltransferase catalyses the first step of histidine biosynthesis and is controlled via a complex allosteric mechanism where the regulatory protein HisZ enhances catalysis by the catalytic protein HisGS while mediating allosteric inhibition by histidine. Activation by HisZ was proposed to position HisGS…
Nan Wu, Sophia N. Yaliraki, Mauricio Barahona
Allostery commonly refers to the mechanism that regulates protein activity through the binding of a molecule at a different, usually distal, site from the orthosteric site. The omnipresence of allosteric regulation in nature and its potential for drug design and screening render the study of allostery invaluable.…
German Mino Galaz, Javier Patino Baez, Nicolas Mino Berdu, Jose Gonzalez Suarez
This research reports the entropy transfer throughout the tridimensional structure of PDZ-2 and TIM barrel structures using the dynamic Gaussian Network Model. The model predicts the allocation of the allosteric pathways of the PDZ-2. Moreover. A visualization analysis reveals that entropy and information is…
Massimo Lai, Denis Brun, Stuart J. Edelstein, Nicolas Le Novère
Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calciumregulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by…
Pedro Pessoa, Steve Pressé, S. Banu Ozkan
Allostery is a fundamental mechanism of protein regulation and is commonly interpreted as modulating enzymatic activity or product abundance. Here we show that this view is incomplete. Using a stochastic model of allosteric regulation combined with an information-theoretic analysis, we quantify the mutual information…
Olga Božović, Jeannette Ruf, Claudio Zanobini, Brankica Janković + 3 more
'David Buhrke' 'Philip J. M. Johnson' 'Peter Hamm'] Abstract: While much is known about different allosteric regulation mechanisms, the nature of the "allosteric signal", and the timescale on which it propagates, remains elusive. The PDZ3 domain from postsynaptic density-95 protein is a small protein domain with a…
D. Thirumalai, Changbong Hyeon, Pavel I. Zhuravlev, George H. Lorimer
'George H. Lorimer'] Allosteric signaling in biological molecules, which may be viewed as specific action at a distance due to localized perturbation upon binding of ligands or changes in environmental cues, is pervasive in biology. Insightful phenomenological MWC and KNF models galvanized research in describing…
Authors not listed
Protein-protein interactions (PPIs) play an essential role in biological processes. Molecules that stabilize or induce PPIs in ternary complexes have received growing attention for their therapeutic potential in engaging ’undruggable’ targets and their high selectivity. Here, we investigate the kinetics and thermody-…
Eric Rouvière, Rama Ranganathan, Olivier Rivoire
Several physical mechanisms have been proposed to explain allostery in proteins. They differ by the number of internal states that they assume a protein to occupy, leaving open the question of what controls the emergence of these distinct physical forms of allostery. Here, we analyze a simplified model of protein…
Christoph Haag, Julia Erl, Korbinian Helbig, Joachim Wegener + 1 more
Cyclic adenosine monophosphate (cAMP) is one of the most prominent molecules involved in intracellular signaling. As a second messenger, it regulates a plethora of biochemical processes that are essential to keep a cell alive and orchestrates physiological responses to external stimuli. Ever since its discovery, great…