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Related Concept Videos

Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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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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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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The Ras Gene02:38

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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.
Ras is a...
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Rab Proteins01:14

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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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Related Experiment Video

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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.

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Researchers developed novel small molecules targeting the K-Ras(G12C) cancer mutation. These inhibitors bind irreversibly, creating a new targetable site and offering a mutant-specific therapeutic strategy.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Somatic mutations in K-Ras are common in cancer, linked to poor treatment outcomes.
  • Directly targeting K-Ras is challenging due to its high affinity for GTP/GDP and lack of known allosteric sites.
  • Oncogenic K-Ras mutations impair GTP hydrolysis, increasing the proportion of active GTP-bound Ras.

Purpose of the Study:

  • To develop small molecules that selectively target the oncogenic K-Ras(G12C) mutant.
  • To identify and validate a novel allosteric binding site on K-Ras(G12C).

Main Methods:

  • Development of irreversible small molecule inhibitors specific to K-Ras(G12C).
  • Crystallographic studies to elucidate the binding mechanism and identify new pockets.
  • Biochemical assays to assess nucleotide binding and effector interactions.

Main Results:

  • Irreversible inhibitors were developed that bind specifically to K-Ras(G12C) via the mutant cysteine.
  • Crystallography revealed a novel binding pocket beneath the switch-II region.
  • Inhibitor binding disrupts switch-I and switch-II, shifting nucleotide preference from GTP to GDP and impairing Raf binding.

Conclusions:

  • A new, mutant-specific allosteric site on K-Ras(G12C) has been identified and validated.
  • These findings provide a structure-based strategy for developing targeted therapies against K-Ras(G12C) mutant cancers.