Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

Lu, Shaoyong; Jang, Hyunbum; Gu, Shuo; Zhang, Jian; Nussinov, Ruth

doi:10.1039/c5cs00911a

Cited by 155 publications

(113 citation statements)

References 245 publications

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“…Since the discovery of the first RAS effector [49,50,51,52], inhibition of RAS signaling by blocking RAS-effector interactions has been an ever-evolving and challenging venture [53,54,55,56]. Biochemical and biophysical studies providing insights into the interaction of the downstream effectors with RAS proteins and their variants established the basic principles for drug design and development [31,43,53,57,58].…”

Section: Discussionmentioning

confidence: 99%

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

Nakhaeizadeh¹,

Amin²,

Nakhaei‐Rad³

et al. 2016

PLoS ONE

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RAS effectors specifically interact with the GTP-bound form of RAS in response to extracellular signals and link them to downstream signaling pathways. The molecular nature of effector interaction by RAS is well-studied but yet still incompletely understood in a comprehensive and systematic way. Here, structure-function relationships in the interaction between different RAS proteins and various effectors were investigated in detail by combining our in vitro data with in silico data. Equilibrium dissociation constants were determined for the binding of HRAS, KRAS, NRAS, RRAS1 and RRAS2 to both the RAS binding (RB) domain of CRAF and PI3Kα, and the RAS association (RA) domain of RASSF5, RALGDS and PLCε, respectively, using fluorescence polarization. An interaction matrix, constructed on the basis of available crystal structures, allowed identification of hotspots as critical determinants for RAS-effector interaction. New insights provided by this study are the dissection of the identified hotspots in five distinct regions (R1 to R5) in spite of high sequence variability not only between, but also within, RB/RA domain-containing effectors proteins. Finally, we propose that intermolecular β-sheet interaction in R1 is a central recognition region while R3 may determine specific contacts of RAS versus RRAS isoforms with effectors.

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Section: Discussionmentioning

confidence: 99%

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

Nakhaeizadeh¹,

Amin²,

Nakhaei‐Rad³

et al. 2016

PLoS ONE

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“…These mutational hotspots comprise amino acids, which are key for the hydrolysis of GTP, and have been developed as prognostic markers and targets for anti-cancer therapies (Pylayeva-Gupta et al, 2011; Chang et al, 2016; Lu et al, 2016). …”

Section: Recurring Mutations In Conserved Septin Residues and Domainsmentioning

confidence: 99%

Septin Mutations in Human Cancers

Angelis

Spiliotis

2016

Front. Cell Dev. Biol.

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Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC) database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4, and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

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“…However, studies that have utilized protein dynamics data such as NMR and mass spectrometry have identified binding pockets on specific K-Ras oncogenic mutants and have attempted to stabilize their conformational states11121314. Accumulating studies suggest that K-Ras proteins are in dynamic and flexible states and their distinct characteristics cannot be identified by structural studies alone12131415161718192021. K-Ras dynamics in different conformational states, that can also change due to allosteric interactions between protein residues, also need to be quantified22.…”

mentioning

confidence: 99%

Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions

Gümüş

Erman

2016

Sci Rep

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K-Ras is the most frequently mutated oncogene in human cancers, but there are still no drugs that directly target it in the clinic. Recent studies utilizing dynamics information show promising results for selectively targeting mutant K-Ras. However, despite extensive characterization, the mechanisms by which K-Ras residue fluctuations transfer allosteric regulatory information remain unknown. Understanding the direction of information flow can provide new mechanistic insights for K-Ras targeting. Here, we present a novel approach –conditional time-delayed correlations (CTC) – using the motions of all residue pairs of a protein to predict directionality in the allosteric regulation of the protein fluctuations. Analyzing nucleotide-dependent intrinsic K-Ras motions with the new approach yields predictions that agree with the literature, showing that GTP-binding stabilizes K-Ras motions and leads to residue correlations with relatively long characteristic decay times. Furthermore, our study is the first to identify driver-follower relationships in correlated motions of K-Ras residue pairs, revealing the direction of information flow during allosteric modulation of its nucleotide-dependent intrinsic activity: active K-Ras Switch-II region motions drive Switch-I region motions, while α-helix-3L7 motions control both. Our results provide novel insights for strategies that directly target mutant K-Ras.

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Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

Cited by 155 publications

References 245 publications

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

Septin Mutations in Human Cancers

Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions

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