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Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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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.
Three regulatory proteins control their activity:
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GTPases and their Regulation02:14

GTPases and their Regulation

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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.
Large G-proteins,...
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GTPases and their Regulation02:14

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No description available
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of 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

The Ras Gene

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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

Rab Proteins

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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.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
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Los inhibidores de K-Ras (G12C) controlan alostéricamente la afinidad GTP y las interacciones efectoras.

Jonathan M Ostrem1, Ulf Peters, Martin L Sos

  • 11] Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2].

Nature
|November 22, 2013
PubMed
Resumen

Los investigadores desarrollaron nuevas moléculas pequeñas dirigidas a la mutación del cáncer K-Ras (G12C). Estos inhibidores se unen de manera irreversible, creando un nuevo sitio objetivo y ofreciendo una estrategia terapéutica específica para los mutantes.

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Área de la Ciencia:

  • Oncología Oncología.
  • Biología Molecular Biología Molecular
  • Descubrimiento de Drogas Descubrimiento de Drogas

Sus antecedentes:

  • Las mutaciones somáticas en K-Ras son comunes en el cáncer, vinculadas a los malos resultados del tratamiento.
  • Dirigirse directamente a K-Ras es un desafío debido a su alta afinidad por GTP / GDP y la falta de sitios alostéricos conocidos.
  • Las mutaciones oncogénicas de K-Ras perjudican la hidrólisis de GTP, aumentando la proporción de Ras. activo ligado al GTP.

Objetivo del estudio:

  • Desarrollar pequeñas moléculas que se dirijan selectivamente al mutante oncogénico K-Ras (G12C).
  • Identificar y validar un nuevo sitio de unión alostérico en K-Ras (G12C).

Principales métodos:

  • Desarrollo de inhibidores irreversibles de moléculas pequeñas específicos para K-Ras (G12C).
  • Estudios cristalográficos para dilucidar el mecanismo de unión e identificar nuevas bolsas.
  • Análisis bioquímicos para evaluar las interacciones de unión de nucleótidos y efectores.

Principales resultados:

  • Se desarrollaron inhibidores irreversibles que se unen específicamente a K-Ras (G12C) a través de la cisteína mutante.
  • La cristalografía reveló un nuevo bolsillo de unión debajo de la región switch-II.
  • La unión del inhibidor interrumpe el switch-I y el switch-II, cambiando la preferencia de nucleótidos de GTP a GDP y perjudicando la unión de Raf.

Conclusiones:

  • Se ha identificado y validado un nuevo sitio alostérico específico de mutantes en K-Ras (G12C).
  • Estos hallazgos proporcionan una estrategia basada en la estructura para desarrollar terapias dirigidas contra los cánceres mutantes K-Ras (G12C).