The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization
Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Abstract
) linker length when targeting certain mTOR variants. In the cryo-EM mTOR/RMC-5552 structure, the distance between the allosteric and orthosteric inhibitors is ∼22.7 Å. With a closed catalytic cleft, this linker bridges the sites. However, in our activation mechanism, in the open cleft it expands to ∼24.7 Å, offering what we believe to be the first direct example of how discovering an activation mechanism can potentially increase the affinity of inhibitors targeting mutants.
Topics & Concepts
Allosteric regulationPI3K/AKT/mTOR pathwayChemistryMechanism (biology)Rendering (computer graphics)Allosteric modulatorCell biologyReceptorStereochemistryComputational biologyBiochemistrySignal transductionComputer scienceBiologyEpistemologyPhilosophyComputer graphics (images)PI3K/AKT/mTOR signaling in cancerClick Chemistry and ApplicationsMonoclonal and Polyclonal Antibodies Research