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Updated: Mar 22, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Unraveling the Deleterious Effects of Cancer-Driven STK11 Mutants Through Conformational Sampling Approach
Merlin Lopus1, D Meshach Paul1, R Rajasekaran1
1Department of Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India.
Abstract:
Tumor suppressor gene, STK11, encodes for serine-threonine kinase, which has a critical role in regulating cell growth and apoptosis. Mutations of the same lead to the inactivation of STK11, which eventually causes different types of cancer. In this study, we focused on identifying those driver mutations through analyzing structural variations of mutants, viz., D194N, E199K, L160P, and Y49D. Native and the mutants were analyzed to determine their geometrical deviations such as root-mean-square deviation, root-mean-square fluctuation, radius of gyration, potential energy, and solvent-accessible surface area using conformational sampling technique. Additionally, the global minimized structure of native and mutants was further analyzed to compute their intramolecular interactions and distribution of secondary structure. Subsequently, simulated thermal denaturation and docking studies were performed to determine their structural variations, which in turn alter the formation of active complex that comprises STK11, STRAD, and MO25. The deleterious effect of the mutants would result in a comparative loss of enzyme function due to variations in their binding energy pertaining to spatial conformation and flexibility. Hence, the structural variations in binding energy exhibited by the mutants, viz., D194N, E199K, L160P, and Y49D, to that of the native, consequently lead to pathogenesis.
Insights
Mutations in the STK11 tumor suppressor gene disrupt cell growth regulation, leading to cancer. This study analyzed specific STK11 mutants, revealing structural changes that impair enzyme function and contribute to disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Genetics
Background:
- The STK11 gene, encoding a serine-threonine kinase, is a crucial tumor suppressor involved in cell growth and apoptosis.
- Mutations in STK11 inactivate its function, contributing to the development of various cancers.
Purpose of the Study:
- To identify driver mutations in STK11 by analyzing structural variations in specific mutants (D194N, E199K, L160P, Y49D).
- To understand how these structural alterations affect STK11 function and its interaction with STRAD and MO25.
Main Methods:
- Conformational sampling techniques to analyze geometrical deviations (RMSD, RMSF, radius of gyration, potential energy, solvent-accessible surface area).
- Analysis of intramolecular interactions and secondary structure distribution.
- Simulated thermal denaturation and molecular docking studies.
Main Results:
- Mutations induced significant geometrical deviations and altered intramolecular interactions and secondary structure.
- Structural variations impacted the formation of the active STK11-STRAD-MO25 complex.
- Mutants exhibited reduced enzyme function due to altered binding energy, spatial conformation, and flexibility.
Conclusions:
- The analyzed STK11 mutants (D194N, E199K, L160P, Y49D) exhibit significant structural variations compared to the native form.
- These structural changes lead to impaired enzyme function and altered binding energies, ultimately contributing to pathogenesis.
- Understanding these mutant structures provides insights into STK11-related cancer development.
