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The Ras Gene

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Related Experiment Video

Updated: Sep 24, 2025

Investigating Protein Sequence-structure-dynamics Relationships with Bio3D-web

Investigating Protein Sequence-structure-dynamics Relationships with Bio3D-web

Published on: July 16, 2017

Delineating the RAS Conformational Landscape.

Mitchell I Parker^1,2, Joshua E Meyer^1,3, Erica A Golemis^1,4

¹Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Research

|May 10, 2022

Summary

This summary is machine-generated.

Researchers have classified RAS protein conformations, revealing new structural insights into mutations and drug interactions. This expanded understanding aids in developing targeted therapies for cancers driven by RAS mutations.

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Area of Science:

Structural biology
Cancer research
Pharmacology

Background:

RAS isoforms (KRAS, NRAS, HRAS) are frequently mutated in cancer, making them critical therapeutic targets.
Targeting RAS requires a deep understanding of its active, inactive, and druggable conformations.
A comprehensive structural catalog of RAS conformations is lacking.

Purpose of the Study:

To develop an expanded classification of RAS conformations.
To analyze the structural impact of common RAS mutations.
To identify druggable RAS conformations for therapeutic targeting.

Main Methods:

Analysis of 721 human RAS structures from the Protein Data Bank.
Classification based on spatial positions of key residues (Y32, Y71) in Switch 1 and Switch 2 loops.
Density-based machine learning for clustering loop conformations.

Main Results:

Defined three Switch 1 and nine Switch 2 conformations.
Associated conformations with nucleotide states (GTP, GDP, nucleotide-free) and binding partners.
Clarified the impact of G12D/G12V mutations and identified inhibitor-binding modes.

Conclusions:

Expanded RAS conformational landscape provides a structural basis for drug discovery.
New insights facilitate the development of targeted therapies for RAS-driven cancers.
Understanding druggable conformations is key to effective RAS-targeted drug design.