Related Experiment Video
Updated: Aug 18, 2026
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Structural basis of p21H-ras molecular switch inhibition by a neutralizing antibody
1Department of Biochemistry, University College Dublin, Belfield, Republic of Ireland.
Abstract:
The ras oncogene product p21 functions as a molecular switch in the early section of the signal transduction pathway that is involved in cell growth and differentiation. When the protein is in its GTP-complexed form it is active in signal transduction, whereas it is inactive in its GDP-complexed form. The transforming activity of p21ras is neutralized by the mouse monoclonal antibody Y13-259, possibly by preventing GDP-GTP exchange. A molecular model of the variable fragment of Y13-259 has been derived using a knowledge-based prediction approach and computer-assisted modeling techniques. An analysis of this model while complexed with p21ras/(GDP) indicated that the two molecular switch regions are constrained by complex formation. Antibody binding inhibits GDP-GTP exchange through a mechanism of steric hindrance. Having identified necessary bound sites for inhibition, and explored their electrostatic properties, it should be possible to proceed with the design of antibody mimics as therapeutic agents in cancer control.
Insights
The ras oncogene product p21, a molecular switch in cell growth, is inactivated by antibody Y13-259, potentially blocking its transforming activity. This study models antibody binding to inhibit GDP-GTP exchange, aiding cancer therapeutic design.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- The ras oncogene product p21 acts as a molecular switch in cell growth and differentiation signaling pathways.
- p21ras is active when bound to GTP and inactive when bound to GDP.
- The monoclonal antibody Y13-259 neutralizes p21ras transforming activity, potentially by inhibiting GDP-GTP exchange.
Purpose of the Study:
- To investigate the mechanism by which antibody Y13-259 neutralizes p21ras transforming activity.
- To develop antibody mimics as potential therapeutic agents for cancer control.
Main Methods:
- Knowledge-based prediction approach.
- Computer-assisted molecular modeling techniques.
- Analysis of the molecular model of the Y13-259 variable fragment complexed with p21ras/(GDP).
Main Results:
- A molecular model of the Y13-259 variable fragment complexed with p21ras/(GDP) was derived.
- Complex formation constrains the molecular switch regions of p21ras.
- Antibody binding inhibits GDP-GTP exchange via steric hindrance.
Conclusions:
- Antibody Y13-259 inhibits p21ras function by sterically hindering GDP-GTP exchange.
- Identifying critical binding sites and their electrostatic properties facilitates the design of antibody mimics.
- These antibody mimics hold promise as therapeutic agents for cancer treatment.
