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Header of Allosteric

Examples of Allosteric

Sentences

81 examples:

Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle.
(Nature, )

Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.
(Nature Communications, )

Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective.
(Nature, )

Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF.
(Nature, )

Conventional allosteric modulators of G protein–coupled receptors (GPCRs) bind their target from the extracellular site.
(Nature Chemical Biology , )

Here, using a high-throughput biochemical screen, Okoye-Okafor et al. identify novel allosteric inhibitors of mutant IDH1.
(Nature Reviews Drug Discovery, )

These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism.
(Nature, )

The nature of the guest can also influence the selectivity of the catalyst, reminiscent of allosteric modulation in enzymes.
(Nature Chemistry, )

In contrast, partial agonist (LUF5834) and an allosteric modulator (HMA) exclusively increase the population of the S3 state.
(Nature, )

We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains.
(Nature, )

New small-molecule inhibitors of the histone methyltransferase PRC2 interfere with the allosteric activation of enzymatic activity.
(Nature Chemical Biology , )

Here the authors use DNA origami to construct an allosteric actuator which can act as signal propagator and an environmental sensor.
(Nature Communications, )

More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.
(Nature, )

This opens the door for true structure-based drug discovery aimed at both novel orthosteric and allosteric subsites of the receptors.
(Nature Chemical Biology , )

The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.
(Nature, )

Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling.
(Nature, )

Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin in clinical trials for treatment of systolic heart failure.
(Nature Communications, )

We characterize three of these mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production.
(Nature, )

NMR analyses now reveal that docking interactions also stimulate ATP binding and phosphotransfer activity of p38α via an allosteric mechanism.
(Nature Structural & Molecular Biology, )

The SAD kinases contain a UBA domain that binds to the kinase domain and has a role in autoinhibition and allosteric activation of the AMPK homoenzyme.
(Nature Communications, )

Compound 15 (Cmpd-15) is an allosteric modulator of the β2 adrenergic receptor (β2AR) that was recently isolated from a DNA-encoded small-molecule library.
(Nature, )

Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor.
(Nature, )

This finding opens new avenues for cancer therapy, but it also highlights that much remains to be learned about the fundamental basis of allosteric regulation.
(Nature Structural & Molecular Biology, )

Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation.
(Nature, )

Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) ameliorates synaptic, circuit and behavioral deficits.
(Nature Neuroscience, )

Allosteric activation and inhibition of PFK1 by over ten metabolites and in response to hormonal signalling fine-tune glycolytic flux to meet energy requirements.
(Nature, )

Here Buey et al . describe a guanine nucleotides regulated molecular mechanism for allosteric communication between the regulatory and catalytic domains of IMPDH.
(Nature Communications, )

Here we report on the development and characterization of what is to our knowledge the first photoswitchable allosteric modulator of a G protein–coupled receptor.
(Nature Chemical Biology , )

The C-terminal NegC domain is involved in binding to the core2 domain and functions as an allosteric element for ISWI to respond to the extranucleosomal DNA length.
(Nature, )

To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-
(Nature, )

The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase.
(Nature, )

The structure of GlyRα3 in complex with a selective potentiator that decreases neuropathic pain in an animal model identifies a novel allosteric regulatory mechanism.
(Nature Structural & Molecular Biology, )

Hsp70 chaperones are essential for cellular proteostasis, and their function depends on allosteric communication between their nucleotide- and substrate-binding domains.
(Nature Communications, )

Here the authors show that C. elegans EGFR is constitutively dimeric and undergoes subtle structural changes upon ligand binding that likely underlie allosteric activation.
(Nature Communications, )

Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker.
(Nature, )

We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent.
(Nature, )

An autonomous chemically driven artificial molecular machine uses information acquired by allosteric interactions combined with an exergonic reaction to know which way to go.
(Nature Nanotechnology, )

Kim et al . use FRET to show that ATP binding preferentially occurs at neighbouring subunits of the hexamer, and identify two allosteric systems that coordinate translocation.
(Nature Communications, )

The combination of computational protein design and single-site saturation mutagenesis enables engineering of allosteric transcription factors to respond to new small molecules.
(Nature Methods, )

Our data reveal the structural basis for PSKR recognition of PSK and allosteric activation of PSKR by PSK, opening up new avenues for the design of PSKR-specific small molecules.
(Nature, )

Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.
(Nature, )

Identification of an allosteric mechanism disrupting the antiapoptotic BH3 binding activity of MCL-1 offers a new approach for targeting the apoptotic resistance of human cancers.
(Nature Structural & Molecular Biology, )

A pre-clinical study reports that the use of the positive allosteric modulator GAT211 enhances the effect of pain-relief chemicals produced by the body in response to stress or injury.
(Science Daily - News, )

Here, the authors use recombinant Abl protein to uncover the molecular mechanism underlying allosteric activation of Abl by its SH2 domain through the regulation of autophosphorylation.
(Nature Communications, )

Shukla et al. model conformational changes in c-src during activation, and identify an allosteric site in an intermediate state that may provide a target for small molecule therapeutics.
(Nature Communications, )

SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism.
(Nature, )

A recent study reveals a tunable allosteric network in group II chaperonins that includes a residue at the intersubunit interface, which is important for assembly and allosteric coordination.
(Nature Structural & Molecular Biology, )

Here, the authors identify a role for bile salts as direct allosteric inhibitors of autotaxin activity, suggesting that steroids may function as regulators of lysophosphatidic acid signalling.
(Nature Communications, )

An allosteric inhibitor of acetyl-CoA carboxylase reveals a metabolic liability of non-small-cell lung cancer and slows tumor growth alone and in combination with chemotherapy in mouse models.
(Nature Medicine, )

The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V–VII near the intracellular half of the receptor.
(Nature, )

The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported.
(Nature, )

Here, the authors present fusions of maltose-binding protein with TEM1 β-lactamase as multi-input allosteric protein switches that can be controlled by temperature and pH in the presence of the effector.
(Nature Communications, )

Yet, important biological systems such as allosteric ligand-receptor binding, macromolecular crowding, or misfolded molecules may not fulfill these assumptions and may require a particular reaction model.
(Science Daily - News, )

Now, a strategy for allosteric activation using coordination chemistry has been demonstrated for two different kinds of neurotransmitter receptors, an ion-channel and a G-protein coupled glutamate receptor.
(Nature Chemistry, )

Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects.
(Nature, )

Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively.
(Nature, )

Through allosteric enhancement of HIF-1α release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations.
(Nature, )

Foda et al . show that reactants and products of the tyrosine kinase Src bind its catalytic domain with opposite cooperativity, and identify an allosteric network of dynamically coupled amino acids that underlie this behaviour.
(Nature Communications, )

Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia.
(Nature, )

Here we report stabilization of two distinct β2AR conformations using single domain camelid antibodies (nanobodies)—a previously described positive allosteric nanobody (Nb80) and a newly identified negative allosteric nanobody (Nb60).
(Nature, )

Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design.
(Nature Structural & Molecular Biology, )

We describe a completely novel allosteric binding site for class B receptors, providing an opportunity for structure-based drug design for this receptor class and furthering our understanding of the mechanisms of activation of these receptors.
(Nature, )

We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R.
(Nature Chemical Biology , )

Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches.
(Nature Reviews Drug Discovery, )

Structural and functional analyses of HopZ1a, a member of the YopJ family of bacterial type III–secreted effectors, reveal the structural basis of YopJ effectors’ noncanonical acetyltransferase activity and allosteric regulation by inositol hexakisphosphate.
(Nature Structural & Molecular Biology, )

This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.
(Nature, )

Here we report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer.
(Nature, )

Structures of a soluble ligand-binding domain have provided atomic-scale insights into receptor–ligand interactions, while high-resolution structures of other members of the pentameric receptor superfamily provide touchstones for an emerging allosteric gating mechanism.
(Nature, )

An allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase—an enzyme that is nonessential for in vitro growth—has potent antimicrobial activity, revealing a potentially expanded target list for antimicrobials and greater chemical space for new inhibitors.
(Nature Chemical Biology , )

The combined analysis of chemical shift changes from the point mutations and ligand responses identifies crucial connections in the allosteric activation pathway, and presents a general experimental method to delineate signal transmission networks at high resolution in GPCRs.
(Nature, )

First, we show that iso-ADP-ribose (iso-ADPr), the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one.
(Nature, )

P2X receptors are ion channels that are controlled by the level of extracellular ATP. Here, Zhao et al. describe the coordinated allosteric changes in two protein domains that couple extracellular ATP-binding to channel gating and show that these changes are essential for the function of the proteins.
(Nature Communications, )

Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.
(Nature, )

Newly synthesized 60S ribosomal subunits are licensed for translation through the release of the antiassociation factor eIF6. A new study shows by cryo–electron microscopy how eIF6 eviction results from a long-range allosteric cascade that involves SBDS, the protein mutated in Shwachman-Diamond syndrome.
(Nature Structural & Molecular Biology, )

The 1,4-dihydropyridines are used primarily for treatment of hypertension and angina pectoris and are thought to act as allosteric modulators of voltage-dependent Ca2+ channel activation, whereas phenylalkylamines and benzothiazepines are used primarily for treatment of cardiac arrhythmias and are thought to physically block the pore.
(Nature, )

Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information.
(Nature, )

Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the β2-adrenergic receptor.
(Nature, )

In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding.
(Nature, )

Here we address the mechanism whereby a tethered vesicle comes closer towards its target membrane for fusion by reconstituting an endosomal asymmetric tethering machinery consisting of the dimeric coiled-coil protein EEA1 (refs 7) recruited to phosphatidylinositol 3-phosphate membranes and binding vesicles harbouring Rab5. Surprisingly, structural analysis reveals that Rab5:GTP induces an allosteric conformational change in EEA1, from extended to flexible and collapsed.
(Nature, )

We find that the agonist isoprenaline has a 15,000-fold higher affinity for β2AR in the presence of Nb80 compared to the affinity of isoprenaline for β2AR in the presence of Nb60, highlighting the full allosteric range of a GPCR. Assessing the binding of 17 ligands of varying efficacy to the β2AR in the absence and presence of Nb60 or Nb80 reveals large ligand-specific effects that can only be explained using an allosteric model which assumes equilibrium amongst at least three receptor states.
(Nature, )

Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity.
(Nature, )

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