Activating mutations drive human MEK1 kinase using a gear-shifting mechanism

Area of Science:

• Biochemistry and structural biology
• Computational biophysics
• Molecular dynamics

Background:

• Kinase mutations drive cancer and RASopathies, but their mechanistic classification is lacking.
• Understanding how mutations alter kinase conformation and function is crucial for therapeutic targeting.
• The human MEK1 kinase, part of the RAS/MAPK pathway, is frequently mutated in cancers and developmental disorders.

Purpose of the Study:

• To explore how cancer-associated mutations affect the human MEK1 kinase at atomic resolution.
• To computationally map conformational stabilities and free energy landscapes of mutated MEK1.
• To connect these computational findings to experimentally determined mutation potentials.

Main Methods:

• Utilized enhanced sampling simulations and free energy calculations.
• Computationally delineated free energy landscapes for mutated MEK1 systems.
• Analyzed alterations in hydrogen bonding networks and residue-level correlations.

Main Results:

• Mutations progressively stabilize the active-like conformation of MEK1 while destabilizing the inactive-like state.
• Free energy landscapes revealed distinct conformational stabilities for each mutation.
• Mutations alter internal molecular correlations, influencing MEK1 activation modes like a gear-shifting mechanism.

Conclusions:

• Mutations leverage conformational plasticity and hydrogen bonding networks to modulate MEK1 activity.
• The study defines the molecular basis for MEK1 activation, linking structure, dynamics, and function.
• This work enhances understanding of MEK1 regulation and the impact of cancer-promoting mutations.