Dual roles of ATP-binding site in protein kinases: Orthosteric inhibition and allosteric regulation.
2021
Protein kinases use ATP to phosphorylate other proteins. Phosphorylation (p) universally orchestrates a fine-tuned network modulating a multitude of biological processes. Moreover, the start of networks, ATP-binding site, has been recognized dual roles to impact protein kinases function: (i) orthosteric inhibition, via being blocked to interference ATP occupying and (ii) allosteric regulation, via being altered first to induce further conformational changes. The above two terminologies are widely used in drug design, which has acquired quite a significant progress in the protein kinases field over the past 2 decades. Most small molecular inhibitors directly compete with ATP to implement orthosteric inhibition, still exhibiting irreplaceable and promising therapeutic effects. Additionally, numerous inhibitors can paradoxically lead protein kinases to hyperphosphorylation, even activation, indicative of the allosteric regulation role of the ATP-binding site. Here, we review the quintessential examples that apply for the dual roles in diverse ways. Our work provides an insight into the molecular mechanisms under the dual roles and will be promisingly instructive for future drug development.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
80
References
2
Citations
NaN
KQI