Structural impact of GTP binding on downstream KRAS signaling

Menyhárd, Dóra K.; Pálfy, Gyula; Orgován, Zoltán; Vida, István; Keserü, György M.; Perczel, András

doi:10.1039/d0sc03441j

Cited by 31 publications

(48 citation statements)

References 82 publications

(127 reference statements)

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“…This also strengthens the hypothesis about the strong impact of A59G mutation on the SwII region. Another recent study also talks about the individual yet crucial impact of specific residues on the structural arrangement for the KRas isoform [65]. The study talks about wild-type, G12C and G12D mutants of KRas and roles of specific residues like Tyr32, Gln61 and Tyr64 in destabilization of water molecules in mutant systems.…”

Section: Discussionmentioning

confidence: 99%

Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas

2020

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The Ras family of proteins is known to play an important role in cellular signal transduction. The oncoprotein Ras is also found to be mutated in ~90% of the pancreatic cancers, of which G12V, G13V, A59G and Q61L are the known hot-spot mutants. These ubiquitous proteins fall in the family of G-proteins, and hence switches between active GTP bound and inactive GDP bound states, which is hindered in most of its oncogenic mutant counterparts. Moreover, Ras being a GTPase has an intrinsic property to hydrolyze GTP to GDP, which is obstructed due to mutations and lends the mutants stuck in constitutively active state leading to oncogenic behavior. In this regard, the present study aims to understand the dynamics involved in the hot-spot mutant A59G-Ras using long 10μs classical MD simulations (5μs for each of the wild-type and mutant systems) and comparing the same with its wild-type counterpart. Advanced analytics using Markov State Model (MSM) based approach has been deployed to comparatively understand the transition path for the wild-type and mutant systems. Roles of crucial residues like Tyr32, Gln61 and Tyr64 have also been established using multivariate PCA analyses. Furthermore, this multivariate PCA analysis also provides crucial features which may be used as reaction coordinates for biased simulations for further studies. The absence of formation of pre-hydrolysis network is also reported for the mutant conformation, using the distance-based analyses (between crucial residues) of the conserved regions. The implications of this study strengthen the hypothesis that the disruption of the pre-hydrolysis network in the mutant A59G ensemble might lead to permanently active oncogenic conformation in the mutant conformers.

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Section: Discussionmentioning

confidence: 99%

Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas

2020

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“…We anticipate application to multiple additional phenomena. Efficient conversion of light energy into proton gradients by membrane proteins like bacteriorhodopsin [142]; transmembrane communication by G-protein coupled receptors [143]; and associated downstream regulatory circuits and intracellular regulation [144] all coordinate ligand binding to allosteric conformational changes. Thus, they appear to require some form of reciprocally coupled gating analogous to that summarized in Figure 2.…”

Section: Conclusion: Strange Loops Tame Eigen's Cliff and The Paradomentioning

confidence: 99%

“…Moreover, most of the systems listed in the previous paragraph are central to pharmacologic intervention. Reciprocally-coupled gating may point to new insights that improve therapeutic regimens in such resistant problem areas as KRAS-linked oncogenesis [144].…”

Section: Conclusion: Strange Loops Tame Eigen's Cliff and The Paradomentioning

confidence: 99%

Reciprocally-Coupled Gating: Strange Loops in Bioenergetics, Genetics, and Catalysis

Carter

Wills

2021

Biomolecules

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Bioenergetics, genetic coding, and catalysis are all difficult to imagine emerging without pre-existing historical context. That context is often posed as a “Chicken and Egg” problem; its resolution is concisely described by de Grasse Tyson: “The egg was laid by a bird that was not a chicken”. The concision and generality of that answer furnish no details—only an appropriate framework from which to examine detailed paradigms that might illuminate paradoxes underlying these three life-defining biomolecular processes. We examine experimental aspects here of five examples that all conform to the same paradigm. In each example, a paradox is resolved by coupling “if, and only if” conditions for reciprocal transitions between levels, such that the consequent of the first test is the antecedent for the second. Each condition thus restricts fluxes through, or “gates” the other. Reciprocally-coupled gating, in which two gated processes constrain one another, is self-referential, hence maps onto the formal structure of “strange loops”. That mapping uncovers two different kinds of forces that may help unite the axioms underlying three phenomena that distinguish biology from chemistry. As a physical analog for Gödel’s logic, biomolecular strange-loops provide a natural metaphor around which to organize a large body of experimental data, linking biology to information, free energy, and the second law of thermodynamics.

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“…[16][17][18][19] Nuclear magnetic resonance (NMR) spectroscopy has become one of the most valuable tools a chemist has, partly due to its extraordinary ability for structural elucidation. [20][21][22][23][24] By understanding the fundamental concepts of NMR spectroscopy (i.e., coupling constant, chemical shift, and integration), scientists can take advantage of this technique to gain insight into the different atoms present in a molecule, such as how they are connected and their relative spatial proximities. 25,26 More recently, NMR spectroscopy has also been applied to quantitative applications (qNMR), particularly in the areas of natural products and medicinal chemistry, because it is non-destructive and inherently quantitative in nature.…”

Section: Introductionmentioning

confidence: 99%

Lithium-7 qNMR as a method to quantify lithium content in brines using benchtop NMR

Araneda

Hui

Leskowitz

et al. 2021

Analyst

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Structural impact of GTP binding on downstream KRAS signaling

Abstract: Oncogenic RAS proteins, involved in ~30% of human tumors, are molecular switches of various signal transduction pathways. Here we apply a new protocol for the NMR study of KRAS in...

Cited by 31 publications

References 82 publications

Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas

Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas

Reciprocally-Coupled Gating: Strange Loops in Bioenergetics, Genetics, and Catalysis

Lithium-7 qNMR as a method to quantify lithium content in brines using benchtop NMR

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