Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition

Wu, Wen-I; Voegtli, W.C.; Sturgis, Hillary L.; Dizon, Faith P.; Vigers, Guy; Brandhuber, Barbara J.

doi:10.1371/journal.pone.0012913

Cited by 283 publications

(317 citation statements)

References 30 publications

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“…Recent structural studies indicate that inhibitory interdomain interactions play a crucial role in regulating AKT activation (15,17). Using a mutational screen, we show here that activation of AKT can result from mutations in residues involved in PH-KD contacts.…”

Section: Discussionmentioning

confidence: 85%

“…Several ATP-competitive and allosteric smallmolecule inhibitors of AKT are in development and/or clinical trials (36,37). Previous studies have shown that allosteric AKT inhibitors require an intact PH-KD interface for their activity (17,(38)(39)(40). Given that some AKT1 somatic mutants have impaired PH-KD contacts, we predicted that allosteric inhibitors are likely to be less efficacious in inhibiting their activity.…”

Section: Disruption Of Akt2 and Akt3 Ph-kd Interactions Leads To Theirmentioning

confidence: 99%

“…Recent molecular modeling and structure-based studies suggest that, under basal conditions, interactions between the PH and KD maintain AKT in a closed conformation (PH-in) (15)(16)(17). In this state, PDK1 is unable to access and phosphorylate T308.…”

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confidence: 99%

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Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Parikh

Janakiraman

et al. 2012

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

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The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH-KD interface and found that most of them lead to constitutive activation of AKT. Such mutations are likely another mechanism by which activation may occur in human cancers and other diseases. In support of this likelihood, we found somatic mutations in AKT1 at the PH-KD interface that have not been previously described in human cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively active, leading to oncogenic signaling. Additionally, our studies show that the AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors, consistent with the requirement for an intact PH-KD interface for allosteric inhibition. These results have important implications for therapeutic intervention in patients with AKT mutations at the PH-KD interface.interdomain | AKT-targeting | PI3K-pathway | next generation sequencing | BaF3

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Section: Discussionmentioning

confidence: 85%

Section: Disruption Of Akt2 and Akt3 Ph-kd Interactions Leads To Theirmentioning

confidence: 99%

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Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Parikh

Janakiraman

et al. 2012

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

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130

160

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“…Thereafter, this complex has been considered during the pharmacophore generation process as model for other pharmacophore realization and to find a promising molecule as lead compound that could become a new potential drug [4].…”

Section: Search In Pdb Database Of a Model Structure For Akt1mentioning

confidence: 99%

Pharmacophore modeling, virtual computational screening and biological evaluation studies

Dotolo

Facchiano

2017

Preprint

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Drug discovery process plays an important role in identifying new investigational drug-likes and developing new potential inhibitors related to a determinate target, in biopharmaceutical field [1]. An alternative promising and efficient used to identify new active substances is Pharmacophore modeling method.We defined a new computational strategy protocol characterized by the use of bioinformatics online tools and by the application of locally installed tools, for lead candidates generation-optimization able to reduce the cycle time and cost of this process and to promote the next steps of study [2].Hence, we have tried to apply this new computational procedure, in a more detailed screening, of small bioactive molecules, searching and identifying new candidates as "lead compounds", potentially able to inhibit biological target AKT1 human protein and its related molecular mechanisms [3].The workflow executed in our work has been characterized by a multi-step design, which concerns different topics: search in PDB database of a model structure for AKT1, pharmacophore modeling and virtual computational screening, biological evaluation divided in two parts (molecular validation of selected compounds and study of physical-chemical properties related to pharmacokinetic/pharmacodynamics prediction models). All these step have been performed through PHARMIT (http://pharmit.csb.pitt.edu) and Discovery Studio 4.5 platform.We selected the PDB structure 3O96 as the reference complex (protein-ligand), and we analyzed it by means of PHARMIT and Discovery Studio, to generate four different "pharmacophore models" with four different list of natural compounds.It is performed a thorough screening of compounds applying several filters, to find some good candidates as possible natural AKT1 allosteric inhibitors.The compounds that match a well-defined pharmacophore have been analyzed through direct molecular docking, for selecting only the best candidates and studying the protein-ligand interactions. Selected compounds have been investigated in more details, to trace their origin, by their chemical-physical properties.This information can help us to predict some plausible enzyme-catalyzed reaction pathways, through PathPred web-server and KEGG compound database, in order to highlight the most important reactions for biosynthesis of compounds and obtain PharmacoKinetics/PharmacoDynamics (PK/PD) models, to investigate the ADMET properties of these lead compounds and to study their behavior in some biological systems, for the next experimental assays.This new computational strategy has been very efficient in showing what could be good "lead compounds" and potential natural inhibitors of AKT1 and PI3K/AKT1 signaling cascade. Therefore, the next steps could be the experimental analysis of pharmacokinetics-pharmacodynamics and toxicity properties "in vitro/in vivo", in order to evaluate the results obtained "in silico".PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2721v1 | CC BY 4.0 Open Access |

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“…A study using transgenic mice showed that overexpression of Akt3-v1 was cardioprotective in a short-term, but eventually resulted in cardiohypertrophy (24). The recently published crystallization data of the Akt2 kinase domain and the protein structure of Akt1 bound to an allosteric inhibitor (Akt1/2 inhibitor VIII) will further facilitate our understanding of the isoform-specific Akt function (25,26).…”

Section: Gene and Amino Acid Sequences Of The Akt Isoformsmentioning

confidence: 99%

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

Santi¹,

Douglas²,

Lee³

2010

BioMolecular Concepts

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Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1-3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

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Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition

Cited by 283 publications

References 30 publications

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Pharmacophore modeling, virtual computational screening and biological evaluation studies

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

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