Allosteric Mechanisms of Signal Transduction

Changeux, Jean‐Pierre; Edelstein, Stuart J.

doi:10.1126/science.1108595

Cited by 690 publications

(581 citation statements)

References 32 publications

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“…cellular localization or content and concentrations of co-regulatory molecules), and liganddependent or independent post-translational modifications, different concentrations of the ligand pools may be required to stabilize the ensemble threshold required to trigger or induce a given intracellular signaling cascade or global cellular event. Finally, while the model presented seems consistent with stereo and shape specific vitamin D sterol-VDR structurefunction results and an overlapping two pocket allosteric model [52], it remains a hypothetical model until true kinetic and/or structural validation is obtained to further substantiate presence of a VDR A-pocket. figure).…”

Section: Discussionsupporting

confidence: 59%

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Recently, we have developed a vitamin D sterol (VDS)-VDR conformational ensemble model. This model can be broken down into three individual, yet interlinked parts: a) the conformationally flexible VDS, b) the apo/holo-VDR helix-12 (H12) conformational ensemble, and c) the presence of two VDR ligand binding pockets (LBPs); one thermodynamically favored (the genomic pocket, Gpocket) and the other kinetically favored by VDSs (the alternative pocket, A-pocket). One focus of this study is to use directed VDR mutagenesis to 1) demonstrate H12 is stabilized in the transcriptionally active closed conformation (hVDR-c1) by three salt-bridges that span the length of H12 (cationic residues R154, K264 and R402), 2) to elucidate the VDR trypsin sites [R173 (hVDRc1), K413 (hVDR-c2) and R402 (hVDR-c3)] and 3) demonstrate the apo-VDR H12 equilibrium can be shifted. The other focus of this study is to apply the model to generate a mechanistic understanding to discrepancies observed in structure-function data obtained with a variety of 1α,25(OH) 2 -vitamin D 3 (1,25D) A-ring and side-chain analogs, and side-chain metabolites. We will demonstrate that these structure-function conundrums can be rationalized, for the most part by focusing on alterations in the VDS conformational flexibility and the elementary interaction between the VDS and the VDR A-and G-pockets, relative to the control, 1,25D.

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Section: Discussionsupporting

confidence: 59%

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…1 Later studies, both in bulk and with single molecule resolution, proposed monomeric proteins to operate through conformational selection. 3,38,40−45 The same mechanism was successfully borrowed for monomeric enzymes to explain substrate mediated conformational redistributions along the reaction coordinate.…”

Section: ■ Conclusionmentioning

confidence: 99%

Single Enzyme Studies Reveal the Existence of Discrete Functional States for Monomeric Enzymes and How They Are “Selected” upon Allosteric Regulation

Hatzakis¹,

Li²,

Jørgensen³

et al. 2012

J. Am. Chem. Soc.

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Allosteric regulation of enzymatic activity forms the basis for controlling a plethora of vital cellular processes. While the mechanism underlying regulation of multimeric enzymes is generally well understood and proposed to primarily operate via conformational selection, the mechanism underlying allosteric regulation of monomeric enzymes is poorly understood. Here we monitored for the first time allosteric regulation of enzymatic activity at the single molecule level. We measured single stochastic catalytic turnovers of a monomeric metabolic enzyme (Thermomyces lanuginosus Lipase) while titrating its proximity to a lipid membrane that acts as an allosteric effector. The single molecule measurements revealed the existence of discrete binary functional states that could not be identified in macroscopic measurements due to ensemble averaging. The discrete functional states correlate with the enzyme's major conformational states and are redistributed in the presence of the regulatory effector. Thus, our data support allosteric regulation of monomeric enzymes to operate via selection of preexisting functional states and not via induction of new ones.

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“…In this study, we found that egonol gentiobioside and egonol gentiotrioside at concentrations of 0.1-1 mM could significantly promote the substrate conversion catalyzed by purified aromatase in vitro, indicating that the binding of these compounds may modulate the protein conformation of aromatase and enhance its substrate conversion efficiency. This positive allosteric effect has been widely found in ligand-binding receptors and enzyme catalysis (Changeux and Edelstein, 2005). It has been reported that aromatase activity is enhanced by posttranslational modification through the mitogen-activated protein kinase or phosphoinositide 3-kinase pathway (Miller et al, 2008;Su et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

Egonol gentiobioside and egonol gentiotrioside from Styrax perkinsiae promote the biosynthesis of estrogen by aromatase

Yang

et al. 2012

European Journal of Pharmacology

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Allosteric Mechanisms of Signal Transduction

Cited by 690 publications

References 32 publications

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Single Enzyme Studies Reveal the Existence of Discrete Functional States for Monomeric Enzymes and How They Are “Selected” upon Allosteric Regulation

Egonol gentiobioside and egonol gentiotrioside from Styrax perkinsiae promote the biosynthesis of estrogen by aromatase

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