Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro biochemical assay and computational molecular dynamics simulations.
PubMed 37185607 · doi:10.1038/s41598-023-33333-6
What was done
Researchers synthesized a synthetic derivative of rotenone locked in a rigid "straight" conformation and compared its inhibitory potency against mitochondrial respiratory complex I relative to natural flexible rotenone. They also conducted large-scale molecular dynamics and free energy simulations to model the ligand-binding pathway, conformer stabilities, and protein structural rearrangements in the substrate-binding Q-channel.
What was found
The straight-locked rotenone derivative inhibited complex I with 600-fold lower potency than natural rotenone. Simulations showed that while the bent conformer is thermodynamically more stable in the membrane and at the redox active site, the straight conformer is required to traverse the narrow entrance of the Q-channel. Rotenone binding also triggered loop and side-chain reconfigurations inside the Q-channel resembling open-to-closed transitions of complex I.
Why it matters
Revealing that dynamic conformational switching between straight and bent forms is required for complex I inhibition provides a structural rationale for tuning synthetic rotenone derivatives for pesticide or therapeutic development.
Limits
The abstract describes purely in vitro and computational biophysical models without testing in living cellular or in vivo animal systems. Absolute inhibitory concentrations (such as IC50 values) and exact simulation sample sizes or replicate counts are not reported in the abstract.
Cited by
- supports The pesticide rotenone specifically targets and impairs mitochondrial functioning.