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Related Concept Videos

Small GTPases - Ras and Rho01:24

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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GTPases and their Regulation02:14

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Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Related Experiment Video

Updated: Jun 29, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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Mutations influence the conformational dynamics of the GDP/KRAS complex.

Congcong Shen1, Jie Yin2, Min Wang2

  • 1Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, China.

Journal of Biomolecular Structure & Dynamics
|March 26, 2024
PubMed
Summary

Mutations near KRAS allosteric sites alter protein flexibility and dynamics. This impacts KRAS binding to regulators and effectors, affecting its overall activity.

Keywords:
GTP/KRAS complexGaMD simulationconformational dynamicsfree energy landscapes

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • Mutations in KRAS, a key regulator of cellular signaling, can lead to significant functional alterations.
  • Allosteric sites are crucial for modulating protein activity, and mutations near these sites warrant detailed investigation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which specific KRAS mutations near allosteric sites influence KRAS activity.
  • To elucidate how these mutations affect KRAS conformational dynamics and interactions with GDP and regulatory partners.

Main Methods:

  • Gaussian accelerated molecular dynamics (GaMD) simulations were employed to enhance conformational sampling.
  • Principal component analysis (PCA) was utilized to analyze the dynamic behavior and correlated motions of KRAS.

Main Results:

  • Selected KRAS mutations (K104Q, G12D/K104Q, G12D/G75A) significantly altered structural flexibility and switch region dynamics.
  • Mutations impacted hydrogen bonding between GDP and switch regions, and affected magnesium ion interactions.
  • These changes were shown to influence KRAS binding to effectors and regulators, thereby allosterically regulating activity.

Conclusions:

  • KRAS mutations near allosteric sites profoundly impact protein dynamics and effector/regulator interactions.
  • The study provides valuable theoretical insights into the allosteric regulation of KRAS function by mutations.
  • Understanding these mechanisms can contribute to the development of targeted therapies for KRAS-related diseases.