Cooperativity and biological complexity

Whitty, Adrian

doi:10.1038/nchembio0808-435

Cited by 270 publications

(250 citation statements)

References 18 publications

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“…Cooperative binding is widely used in nature to enhance specific processes such as protein folding, polymerization, and ligand binding (Perutz 1989;Whitty 2008). Proteins that use cooperative activity have been identified in multisubunit enzymes and receptors (Bohr et al 1904;Koshland and Hamadani 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Proteins that use cooperative activity have been identified in multisubunit enzymes and receptors (Bohr et al 1904;Koshland and Hamadani 2002). Cooperativity can operate at many different levels, but in particular, allosteric cooperativity involves a ''receptor'' that contains two or more ligand-binding sites, in which ligand binding at one site affects the ligand affinity at the other site (Whitty 2008). The Hill coefficient provides a method for quantifying the degree of cooperativity of ligand binding to the macromolecule (Hill 1910).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a tertiary interaction important for cooperative ligand binding by the glycine riboswitch

Erion¹,

Strobel²

2010

RNA

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The glycine riboswitch has a tandem dual aptamer configuration, where each aptamer is a separate ligand-binding domain, but the aptamers function together to bind glycine cooperatively. We sought to understand the molecular basis of glycine riboswitch cooperativity by comparing sites of tertiary contacts in a series of cooperative and noncooperative glycine riboswitch mutants using hydroxyl radical footprinting, in-line probing, and native gel-shift studies. The results illustrate the importance of a direct or indirect interaction between the P3b hairpin of aptamer 2 and the P1 helix of aptamer 1 in cooperative glycine binding. Furthermore, our data support a model in which glycine binding is sequential; where the binding of glycine to the second aptamer allows tertiary interactions to be made that facilitate binding of a second glycine molecule to the first aptamer. These results provide insight into cooperative ligand binding in RNA macromolecules.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a tertiary interaction important for cooperative ligand binding by the glycine riboswitch

Erion¹,

Strobel²

2010

RNA

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“…small changes in molecular concentration (9,13), can be applied in applications, such as biosensing (14,15), "smart" drug delivery materials (16,17), and molecular (18) and genetic (19) logic gates, in which such enhanced responsiveness would be of value.…”

mentioning

confidence: 99%

Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors

Simon

Vallée‐Bélisle

Ricci

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Control over the sensitivity with which biomolecular receptors respond to small changes in the concentration of their target ligand is critical for the proper function of many cellular processes. Such control could likewise be of utility in artificial biotechnologies, such as biosensors, genetic logic gates, and "smart" materials, in which highly responsive behavior is of value. In nature, the control of molecular responsiveness is often achieved using "Hilltype" cooperativity, a mechanism in which sequential binding events on a multivalent receptor are coupled such that the first enhances the affinity of the next, producing a steep, higher-order dependence on target concentration. Here, we use an intrinsicdisorder-based mechanism that can be implemented without requiring detailed structural knowledge to rationally introduce this potentially useful property into several normally noncooperative biomolecules. To do so, we fabricate a tandem repeat of the receptor that is destabilized (unfolded) via the introduction of a long, unstructured loop. The first binding event requires the energetically unfavorable closing of this loop, reducing its affinity relative to that of the second binding event, which, in contrast occurs at a preformed site. Using this approach, we have rationally introduced cooperativity into three unrelated DNA aptamers, achieving in the best of these a Hill coefficient experimentally indistinguishable from the theoretically expected maximum. The extent of cooperativity and thus the steepness of the binding transition are, moreover, well modeled as simple functions of the energetic cost of binding-induced folding, speaking to the quantitative nature of this design strategy. ultrasensitivity | intrinsically disordered proteins | biosensors | synthetic biology | ribozymes

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“…It also demonstrates potential to link fragments together, a non-trivial task. [64] Figure 10 Tethering with dynamic extenders. Diaminopyrimidine 17 was incubated with mixtures of disulfides, of which disulfide 18 is an example, under partially reducing conditions in the presence of aurora A kinase.…”

Section: Aurora Kinase -Tethering With Dynamic Extendersmentioning

confidence: 99%

Kinetic Template‐Guided Tethering of Fragments

2012

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This thesis is composed of two separate projects: Kinetic Template-Guided Tethering of Fragments and Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1 Degradation after DNA Damage. Kinetic Template-Guided Tethering of FragmentsThe development of a novel methodology for the site-directed discovery of small molecule, protein-binding ligands is described. The protein of interest, with a cysteine thiol (either native or engineered) adjacent to the desired binding pocket, is incubated with mixtures of low molecular weight compounds (fragments) modified with either an acrylamide or a vinyl sulfonamide capture group. Any ligand within the mixture that binds within the pocket brings the capture group into close proximity with the cysteine thiol, promoting a conjugate addition reaction at an increased rate over the background reaction. The capture reaction is designed to be slow, such that during the time course of an experiment, no adduct formation is observed unless the reaction is templated by the protein. By this method, binding ligands are rapidly identified by mass spectrometry analysis of the crude reaction mixtures. The methodology has been termed 'kinetic template-guided tethering'. Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1Degradation after DNA Damage An inhibitor described within the literature was found to attenuate the reduction of cyclin D1 after DNA damage to cells. In order to implement a two-step chemical proteomics strategy to find the molecular target of this inhibitor, a synthesis of the compound with an alkyne appendage was required. The alkyne acts as a functional handle for attachment of a reporter molecule in cells via the Huisgen cycloaddition ('Click') reaction. The design and synthesis of this inhibitor with the alkyne appendage is described.

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Cooperativity and biological complexity

Cited by 270 publications

References 18 publications

Identification of a tertiary interaction important for cooperative ligand binding by the glycine riboswitch

Identification of a tertiary interaction important for cooperative ligand binding by the glycine riboswitch

Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors

Kinetic Template‐Guided Tethering of Fragments

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