ArticleFrontiers in molecular biosciences2020
Nucleotide-Specific Autoinhibition of Full-Length K-Ras4B Identified by Extensive Conformational Sampling.
Article in Frontiers in molecular biosciences, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Recent breakthroughs in understanding the allosteric features of Ras GTPases and their effector and regulatory protein interactions, enabling drug design.Current opinion in structural biology · 2026Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophysical journal · 2024Article
- Small GTPase Ran: Depicting the nucleotide-specific conformational landscape of the functionally important C-terminus.Frontiers in molecular biosciences · 2023Article
- Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces.Biophysical journal · 2022Article
- Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations.Physical chemistry chemical physics : PCCP · 2022Article
- ABCG2/BCRP transport mechanism revealed through kinetically excited targeted molecular dynamics simulations.Computational and structural biotechnology journal · 2022Article
- Sampling of Protein Conformational Space Using Hybrid Simulations: A Critical Assessment of Recent Methods.Frontiers in molecular biosciences · 2022Article
- Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations.Scientific reports · 2021Article
- Revealing the activation mechanism of autoinhibited RalF by integrated simulation and experimental approaches.Scientific reports · 2021Article
- Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.Biophysical journal · 2021Article
Corrections and comments
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Authors and funding
6 authors at 6 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
K-Ras is one of the most frequently mutated oncogenes in human tumor cells. It consists of a well-conserved globular catalytic domain and a flexible tail-like hypervariable region (HVR) at its C-terminal end. It plays a key role in signaling networks in proliferation, differentiation, and survival, undergoing a conformational switch between the active and inactive states. It is regulated through the GDP-GTP cycle of the inactive GDP-bound and active GTP-bound states. Here, without imposing any prior constraints, we mapped the interaction pattern between the catalytic domain and the HVR using Molecular Dynamics with excited Normal Modes (MDeNM) starting from an initially extended HVR conformation for both states. Our sampling captured similar interaction patterns in both GDP- and GTP-bound states with shifted populations depending on the bound nucleotide. In the GDP-bound state, the conformations where the HVR interacts with the effector lobe are more populated than in the GTP-bound state, forming a buried thus autoinhibited catalytic site; in the GTP-bound state conformations where the HVR interacts with the allosteric lobe are more populated, overlapping the α3/α4 dimerization interface. The interaction of the GTP with Switch I and Switch II is stronger than that of the GDP in line with a decrease in the fluctuation upon GTP binding.
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