State-selective frustration as a key driver of allosteric pluripotency

Byun, Jung Ah; VanSchouwen, Bryan; Parikh, Nishi; Akimoto, Madoka; McNicholl, Eric Tyler; Melacini, Giuseppe

doi:10.1039/d1sc01753e

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…4). 10,11,[31][32][33][34][35] While this oxygen-to-sulfur substitution may appear relatively subtle, the functional implications are quite dramatic. In the presence of excess MgATP, Rp acts as a very effective antagonist even at mM Rp concentrations.…”

Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

“…34 While the original observation of allosteric pluripotency for Rp dates back around three decades, 34 an explanation of the underlying molecular mechanism of action has become available only recently. 10,11 A first important step in this direction has been the crystal structure of a two-CNBD construct of the R-subunit in complex with two equivalents of Rp (R:Rp 2 ). 28,36 Interestingly, the conformation of this ternary complex was found to be highly similar to its cognate complex with cAMP (R:cAMP 2 ; root mean square deviation ∼0.5 Å; Fig.…”

Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

“…The EAM is parametrized through further ad hoc NMR experiments, such as ligand titrations and H/D exchange. 11,12 The parametrized EAM model allows for quantitative predictions of kinase activation, which are tested through enzymatic assays. 29,[37][38][39] The functional validation of the EAM model informs the design of new protein mutants or ligand analogs to be investigated through a new iteration of the three-pronged ThermoDynamic cycle (Fig.…”

Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

“…[6][7][8][9] Once an allosteric ligand for a given allosteric pocket is identified as a potent and selective inhibitor of a kinase target, another challenge remains due to allosteric pluripotency. [10][11][12][13][14] The response of a kinase to an allosteric modulator is pluripotent when it depends on the specific metabolic and proteomic environment (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

“…3). 10,11,14,[26][27][28][29] The critical segment of R needed to bind C spans an inhibitory site (IS) and two tandem homologous cyclic nucleotide-binding domains (CNBD-A and B; Fig. 3).…”

Section: Introductionmentioning

confidence: 99%

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Allosteric regulation of cyclic nucleotide-dependent protein kinases

et al. 2022

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Kinases include a wide variety of valuable drug targets, but full therapeutic exploitation requires a high degree of selectivity. A promising avenue to engineer the desired kinase selectivity relies on allosteric sites. Here we provide a focused minireview of recent progress in allosteric modulation of cyclic nucleotide-dependent kinases, including protein kinases A and G. We show how apparently diverse emerging concepts such as allosteric pluripotency, allosteric non-additive binding and uncompetitive allosteric inhibition are all manifestations of complex conformational ensembles. Such ensembles include not only the typical apo-inactive and effector-bound-active states, but also mixed intermediates that feature attributes of the former states within a single molecule. We also discuss how allosteric responses are amplified by aggregation processes, thus establishing a novel interface between the signaling and amyloid fields. Finally, we critically evaluate the challenges and opportunities for clinical translation opened by these emerging allosteric concepts.

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Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

Section: Allosteric Modulation Of Pkamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…3). 10,11,14,[26][27][28][29] The critical segment of R needed to bind C spans an inhibitory site (IS) and two tandem homologous cyclic nucleotide-binding domains (CNBD-A and B; Fig. 3).…”

Section: Introductionmentioning

confidence: 99%

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Allosteric regulation of cyclic nucleotide-dependent protein kinases

et al. 2022

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Amyloid-Driven Allostery

Garcha,

Huang,

Martinez Pomier

et al. 2024

Biophysical Chemistry

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Divergent allostery reveals critical differences between structurally homologous regulatory domains of Plasmodium falciparum and human protein kinase G

Byun

VanSchouwen

Huang

et al. 2022

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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State-selective frustration as a key driver of allosteric pluripotency

Abstract: Allosteric pluripotency arises when an allosteric effector switches from agonist to antagonist depending on the experimental conditions. For example, the Rp-cAMPS ligand of Protein Kinase A (PKA) switches from agonist...

Cited by 9 publications

References 51 publications

Allosteric regulation of cyclic nucleotide-dependent protein kinases

Allosteric regulation of cyclic nucleotide-dependent protein kinases

Amyloid-Driven Allostery

Divergent allostery reveals critical differences between structurally homologous regulatory domains of Plasmodium falciparum and human protein kinase G

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