The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

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

doi:10.1038/srep21949

Cited by 153 publications

(170 citation statements)

References 68 publications

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“…However, both the loop regions show significantly lower fluctuations upon nucleotide binding as compared to the nucleotide free state, which signifies the role of these regions in nucleotide binding and/or effector recognition. Earlier simulation studies have shown that mutations in the p-loop or switch regions can significantly alter the degree of flexibility of these regions36373839. A point mutation (P29V) locks the RAC1 in the GTP bound activated state, accompanied by the enhanced flexibility in the SWI region and rigidity in the SWII region36.…”

Section: Resultsmentioning

confidence: 99%

Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

Kumawat

Chakrabarty

Kulkarni

2017

Sci Rep

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Ras superfamily of GTPases regulate myriad cellular processes through a conserved nucleotide (GTP/GDP) dependent switching mechanism. Unlike Ras family of GTPases, for the Rho GTPases, there is no clear evidence for the existence of “sub-states” such as state 1 & state 2 in the GTP bound form. To explore the nucleotide dependent conformational space of the Switch I loop and also to look for existence of state 1 like conformations in Rho GTPases, atomistic molecular dynamics and metadynamics simulations on RhoA were performed. These studies demonstrate that both the nucleotide-free state and the GDP bound “OFF” state have very similar conformations, whereas the GTP bound “ON” state has unique conformations with signatures of two intermediate states. The conformational free energy landscape for these systems suggests the presence of multiple intermediate states. Interestingly, the energetic penalty of exposing the non-polar residues in the GTP bound form is counter balanced by the favourable hydrogen bonded interactions between the γ-phosphate group of GTP with the highly conserved Tyr34 and Thr37 residues. These competing molecular interactions lead to a tuneable energy landscape of the Switch I conformation, which can undergo significant changes based on the local environment including changes upon binding to effectors.

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Section: Resultsmentioning

confidence: 99%

Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

Kumawat

Chakrabarty

Kulkarni

2017

Sci Rep

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“…Because in the G12D mutation, glycine residue is substituted by aspartate, which has a bulkier side group, it causes a structural change in the P-loop which affects the conformations of the other active site regions SI and SII, as observed in previous studies [22][23][24]59 . Our distance calculations show that after G12D mutation, the P-loop residues 11, 12, 13 move away from SII residue Q61.…”

Section: Discussionmentioning

confidence: 77%

“…Yet, despite decades of research, there are still no drugs in the clinic today that can directly target mutant K-Ras 19,20 . Although the effects of G12D mutation on the structure, conformation and flexibility of K-Ras have been studied [21][22][23][24] , the relationship between its conformational and dynamical changes still remains to be understood. At the same time, there is increasing evidence that suggests that crystal structure studies alone may miss drugbinding pockets on mutant K-Ras surface 18,[25][26][27][28][29][30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies suggest that utilizing protein dynamics data is a successful approach for understanding the effects of mutations on the structure, dynamics and function of proteins [34][35][36] . Particularly in drug discovery, dynamics data from oncogenic proteins 22,[37][38][39][40] have helped identify cryptic or allosteric binding sites [41][42][43][44] . We hypothesized that dynamic regulatory mechanisms can best be explored by detailed analyses of their molecular dynamics (MD) simulation data, from which we can predict the regulatory relationships between residue pairs.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Erman

Gümüş

2017

Preprint

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K-Ras is the most frequently mutated protein in human tumors. Activating K-Ras mutations drive cancer initiation, progression and drug resistance, directly leading to nearly a million deaths per year. To understand the mechanisms by which mutations alter K-Ras function, we need to understand their effects on protein dynamics. However, despite decades of research, how oncogenic mutations in K-Ras alter its conformation and dynamics remain to be understood. Here, we present how the most recurrent K-Ras oncogenic mutation, G12D, leads to structural, conformational and dynamical changes that lead to constitutively active KRas. We have developed a new integrated MD simulation data analysis approach to quantify such changes in a protein and applied it to K-Ras. Our results show that G12D mutation induces strong negative correlations between the fluctuations of SII and those of the P-loop, Switch I (SI) and α3 regions in K-Ras G12D . Furthermore, characteristic decay times of SII fluctuations significantly increase after G12D mutation. We have further identified causal relationships between correlated residue pairs in K-Ras G12D and show that the correlated motions in K-Ras dynamics are driven by SII fluctuations, which have the strongest negative correlations with other protein parts and the longest characteristic decay times in mutant KRas. Ours is arguably the first study that shows the causal relationships between residue pairs in K-Ras G12D , relates them to the decay times and correlates their fluctuations.

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“…31 P NMR and X-ray crystallographic data from Shima et al ., 69–71 together with MD simulations from our group, 152 showed that GppNHp-bound H-Ras in solution contains two interconverting conformations, “inactive” state 1 and “active” state 2; the former has a weak binding affinity for effector proteins, while the latter has a strong binding affinity for effector proteins. 68,153 31 P NMR spectroscopy revealed that the conformational ensemble of GppNHp-bound H-Ras in solution shifts towards the weak binding state 1 upon binding of Zn 2+ –1,4,7,10-tetraazacyclodecane (Zn 2+ –cyclen, 2 ) (Fig.…”

Section: Allosteric Inhibition Of Ras By Targeting Its Allosteric Smentioning

confidence: 98%

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 Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

Cited by 153 publications

References 68 publications

Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

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