The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

Lu, Shaoyong; Deng, Rong; Jiang, Haiming; Song, Huihui; Li, Shuai; Shen, Qiancheng; Huang, Wenkang; Nussinov, Ruth; Yu, Jianxiu; Zhang, Jian

doi:10.1016/j.str.2015.06.027

Cited by 62 publications

(65 citation statements)

References 49 publications

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“…Examples include the AMP-activated protein kinase (AMPK), where the engagement of an autoinhibitory domain with the catalytic domain shifts the kinase to an autoinhibited state with much lower activity than that of the kinase domain alone (54). In Akt, the pleckstrin homology domain couples with the kinase domain to lock the Akt in an inactive conformation (55,56). In c-Abl-tyrosine kinase, the N-terminal SH3-SH2 domains, acting as an autoinhibitory "cap," binds to the kinase domain, and the loss of this autoinhibition turns c-Abl into an oncogenic protein (57).…”

Section: Discussionmentioning

confidence: 99%

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

Banerjee²,

Jang

et al. 2015

Journal of Biological Chemistry

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Background:The HVR is important in K-Ras4B signaling. Results: GTP binding and oncogenic mutations may weaken the HVR-catalytic core interactions. Conclusion: GTP and some oncogenic mutations (e.g. G12C/G12V/Q61H/E37K) could attenuate HVR-catalytic domain interactions at the switch I/effector binding site by direct or longer-range interactions. Significance: GTP and specific mutations could prompt exposure of switch I/effector binding site, thereby up-regulating signaling.

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Section: Discussionmentioning

confidence: 99%

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

Banerjee²,

Jang

et al. 2015

Journal of Biological Chemistry

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“…The use of MD simulations coupled with experiments has recently successfully allowed the identification of allosteric networks on other protein kinases. 11–13 …”

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confidence: 99%

Electrostatic Interactions as Mediators in the Allosteric Activation of Protein Kinase A RIα

et al. 2017

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Close-range electrostatic interactions that form salt bridges are key components of protein stability. Here we investigate the role of these charged interactions in modulating the allosteric activation of protein kinase A (PKA) via computational and experimental mutational studies of a conserved basic patch located in the regulatory subunit's B/C helix. Molecular dynamics simulations evidenced the presence of an extended network of fluctuating salt bridges spanning the helix and connecting the two cAMP binding domains in its extremities. Distinct changes in the flexibility and conformational free energy landscape induced by the separate mutations of Arg239 and Arg241 suggested alteration of cAMP-induced allosteric activation and were verified through in vitro fluorescence polarization assays. These observations suggest a mechanical aspect to the allosteric transition of PKA, with Arg239 and Arg241 acting in competition to promote the transition between the two protein functional states. The simulations also provide a molecular explanation for the essential role of Arg241 in allowing cooperative activation, by evidencing the existence of a stable interdomain salt bridge with Asp267. Our integrated approach points to the role of salt bridges not only in protein stability but also in promoting conformational transition and function.

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“…179–185 This effect results in growth inhibition and apoptosis of cancer cells. Because of the large interface area of Ras–effector PPIs and the relatively flat PPI interfaces, it is highly challenging to design small molecule inhibitors bound to PPI interfaces.…”

Section: Inhibition Of Ras By Targeting Ras–effector Protein-proteimentioning

confidence: 99%

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

et al. 2016

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Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras–effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.

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The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

Cited by 62 publications

References 49 publications

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

Electrostatic Interactions as Mediators in the Allosteric Activation of Protein Kinase A RIα

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

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