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SI/II Pocket of Ras: An Opportunity for a Once "Undruggable" Target.

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Ras mutations drive cancer, but the SI/II pocket offers a new therapeutic target. This pocket is accessible in the GTP-bound state, suggesting it’s a promising site for novel Ras inhibitors.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Ras GTPases are key oncogenic drivers, particularly HRas in head-and-neck and genitourinary cancers.
  • The previously undruggable Ras family now presents a potential target: the conserved SI/II pocket near the SOS1 binding site.

Purpose of the Study:

  • To characterize the SI/II pocket's topology in GDP-bound HRasG12V.
  • To investigate the conformational dynamics of the SI/II pocket in different HRas states.

Main Methods:

  • Generated a crystal structure of native GDP-bound HRasG12V.
  • Utilized molecular dynamics simulations on native and synthetic HRas models.
  • Analyzed structures of GDP-bound and GppNHp-bound HRasG12V.

Main Results:

  • The SI/II pocket is inaccessible in native GDP-bound HRas.
  • The pocket becomes accessible in the GppNHp-bound state, especially in mutated HRas.
  • The α2 helix and residue Y71 control pocket accessibility via a 'tyrosine toggle' mechanism.

Conclusions:

  • The GTP-bound state of HRas is the most promising target for SI/II pocket-directed Ras inhibitors.
  • Understanding the SI/II pocket's dynamics is crucial for developing pan-Ras drugs.