Ras: structural details to guide direct targeting

Mattos, Carla

doi:10.18632/aging.100754

Cited by 4 publications

(4 citation statements)

References 7 publications

(10 reference statements)

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“…These observations suggest that the interactions of Ca(OAc) 2 with residues in helix α3, loop L7, and helix α4 trigger conformational changes in the allosteric lobe of H-Ras that can transmit to the effector lobe to order the switch II region. 241 Under these circumstances, the catalytic residue Q61 in the ordered switch II region can interact with the bridging water molecule (W189), which in turn interacts with the side chain of Y32 and γ-phosphate (Figure 26C), rendering the H-Ras−GTP in its precatalytic conformation at the beginning of the hydrolysis reaction. In this context, the H-Ras WT −GppNHp−Ca(OAc) 2 structure represents a catalytically competent state ("on" conformation), while the H-Ras WT −GppNHp−CaCl 2 structure represents a catalytically incompetent state ("off" conformation).…”

Section: Allosteric Switch Of Ras−gtp To the Onmentioning

confidence: 99%

“…In addition, the two oxygen atoms of acetate form hydrogen bonds with the side chain of R97 on helix α3 and the backbone NH group of V109 on loop L7, respectively. These observations suggest that the interactions of Ca(OAc) 2 with residues in helix α3, loop L7, and helix α4 trigger conformational changes in the allosteric lobe of H-Ras that can transmit to the effector lobe to order the switch II region . Under these circumstances, the catalytic residue Q61 in the ordered switch II region can interact with the bridging water molecule (W189), which in turn interacts with the side chain of Y32 and γ-phosphate (Figure C), rendering the H-Ras–GTP in its precatalytic conformation at the beginning of the hydrolysis reaction.…”

Section: Allosteric Switch Of Ras–gtp To the On Statementioning

confidence: 99%

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Ras Conformational Ensembles, Allostery, and Signaling

Jang

Muratcioglu³

et al. 2016

Chem. Rev.

268

301

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Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.

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Section: Allosteric Switch Of Ras−gtp To the Onmentioning

confidence: 99%

Section: Allosteric Switch Of Ras–gtp To the On Statementioning

confidence: 99%

Ras Conformational Ensembles, Allostery, and Signaling

Jang

Muratcioglu³

et al. 2016

Chem. Rev.

268

301

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“…Ras often functions at downstream of Src and exists in two conformations: a GTP-bound active state and GDPbound inactive state. Ratios of GTP-and GDP-bound Ras are controlled by guanine nucleotide exchange proteins and GTPase-activating proteins, the activity of which responds to activation of extracellular (such as growth factors) or intracellular receptors (like Src) [19][20][21][22]. Once interacting with the effectors, signals generated from Ras influence cell growth, migration and other activities.…”

Section: Introductionmentioning

confidence: 99%

PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance

Ganapathy

Liu

et al. 2022

Aging

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Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions. The role of protein kinase C (PKC, an important signal transducer) in Cr (VI)-mediated carcinogenesis has not been thoroughly investigated. In this study, using human bronchial/lung epithelial cells and keratinocytes, we demonstrate that PKC activity is increased by transient or chronic Cr(VI) exposure, which plays no role in the activation of Src/Ras signaling and ROS upregulation by this metal toxin. PKC in chronic Cr(VI)-treated cells stabilizes Bcl-2 to mitigate doxorubicin (an anti-cancer drug)mediated apoptosis. After the suppression of this kinase by GO6976 (a PKC inhibitor), the cells chronically exposed to Cr(VI) partially regain the sensitivity to doxorubicin. However, when co-suppressed PKC and Ras, the chronic Cr(VI)-treated cells become fully responsive to doxorubicin and are unable to be transformed. Taken together, our study provides a new insight into the mechanisms, in which PKC is an indispensable player and cooperates with other mitogenic pathways to achieve Cr(VI)-induced carcinogenesis as well as to establish drug resistance. The data also suggest that active PKC can serve as a potential biomarker for early detection of health damages by Cr(VI) and therapeutic target for developing new treatments for diseases caused by Cr(VI).

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“…Given their central role in oncogenesis, RAS has been spotlighted as an intriguing target for anticancer drug development, and the inhibition of RAS proteins has been considered a promising direction in oncology 17 , 18 , 26 , 27 , 28 . However, many failures occur in the earlier exploration, in large part ascribed to the picomolar affinity of RAS for guanine nucleotide and lack of deep hydrophobic pockets amenable for small molecule ligands, leading to an ‘undruggable’ portrait of RAS 3 , 18 .…”

Section: Introductionmentioning

confidence: 99%

Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators

Qiu

Wang

Chai

et al. 2021

Acta Pharmaceutica Sinica B

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RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an ‘undruggable’ feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

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Ras: structural details to guide direct targeting

Cited by 4 publications

References 7 publications

Ras Conformational Ensembles, Allostery, and Signaling

Ras Conformational Ensembles, Allostery, and Signaling

PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance

Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators

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