Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling

Leroux, Alejandro E.; Gross, Lissy Zoe Florens; Sacerdoti, Mariana; Biondi, Ricardo M.

doi:10.1007/978-981-13-8719-7_12

Cited by 5 publications

(3 citation statements)

References 109 publications

(184 reference statements)

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“…This argues for allosteric drugs. [27][28][29][30][31][32][33][34] Unfortunately, these efforts are yet to produce effective drugs. Notwithstanding, the encouraging successes with KRas4B, another hitherto undruggable oncogenic protein, where creative covalent allosteric drugs target KRas4B G12C , and discovery of new PI3Ka pockets, 27 breed cautious optimism.…”

Section: Allostery Plays a Role In Pi3ka Activation By Rtk But Not Bmentioning

confidence: 99%

PI3K inhibitors: review and new strategies

2020

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Section: Allostery Plays a Role In Pi3ka Activation By Rtk But Not Bmentioning

confidence: 99%

PI3K inhibitors: review and new strategies

2020

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“…Protein kinases are important pharmacological targets ( 31 ) and contain conserved ATP/ADP binding pockets regulated by allosteric switches to fine-tune their enzymatic activity ( 62 ). Most drug candidates are screened against the unliganded apo protein and compounds identified target the conserved ATP-binding pocket making them prone to cross talk interactions with other kinases causing reduced specificity and potency ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Allostery in Multiligand-Protein Interactions

Ghode

Gross

Tee

et al. 2020

Biophysical Journal

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Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIFpocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the aB-aC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved b-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligandbinding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of aC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.

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“…Hence, PDK1 is overexpressed in a variety of human cancers, contributing to the proliferation, migration, and dissemination of tumor cells . For this reason, PDK1 has become a target for cancer therapy. − …”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Regulation of 3-Phosphoinositide-Dependent Protein Kinase 1: Modeling the Interaction between the Kinase and the Pleckstrin Homology Domains

et al. 2022

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The 3-phosphoinositide-dependent protein kinase 1 (PDK1) K465E mutant kinase can still activate protein kinase B (PKB) at the membrane in a phosphatidylinositol-3,4,5-trisphosphate (PIP 3 , PtdIns(3,4,5)P 3 ) independent manner. To understand this new PDK1 regulatory mechanism, docking and molecular dynamics calculations were performed for the first time to simulate the wild-type kinase domain–pleckstrin homology (PH) domain complex with PH-in and PH-out conformations. These simulations were then compared to the PH-in model of the KD–PH(mutant K465E) PDK1 complex. Additionally, three KD–PH complexes were simulated, including a substrate analogue bound to a hydrophobic pocket (denominated the PIF-pocket) substrate-docking site. We find that only the PH-out conformation, with the PH domain well-oriented to interact with the cellular membrane, is active for wild-type PDK1. In contrast, the active conformation of the PDK1 K465E mutant is PH-in, being ATP-stable at the active site while the PIF-pocket is more accessible to the peptide substrate. We corroborate that both the docking-site binding and the catalytic activity are in fact enhanced in knock-in mouse samples expressing the PDK1 K465E protein, enabling the phosphorylation of PKB in the absence of PIP 3 binding.

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Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling

Cited by 5 publications

References 109 publications

PI3K inhibitors: review and new strategies

PI3K inhibitors: review and new strategies

Synergistic Allostery in Multiligand-Protein Interactions

Molecular Insights into the Regulation of 3-Phosphoinositide-Dependent Protein Kinase 1: Modeling the Interaction between the Kinase and the Pleckstrin Homology Domains

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