- Javier Coloma
- Ana I. Hernández
- María Ibarra
- Andrés López
- Ángel Rivera
- Marina Serna
- Sofía Cabezudo
- Alba Ruiz
- Carlos Fernández
- Ana González
Activation and assembly of many protein complexes implicated in cancer, such as kinases and polymerases, require the assistance of HSP90, a molecular chaperone. Thus, HSP90 inhibitors are being evaluated as anticancer agents.
HSP90 is needed for the activation and stability of the PI3- kinase-like kinases (PIKKs), including mTOR, ATM and ATR that regulate the DNA damage response and cell growth. Surprisingly, these kinases require the action of HSP90 but working in concert with the R2TP/Prefoldin-like (R2TP/ PFDL) complex. R2TP/PFDL is the most complex HSP90 co-chaperone yet described. R2TP/PFDL contains multiple subunits and growing evidence links this complex to cancer.
Yet, how all these processes work is largely unknown. We are using cryo-electron microscopy (cryo-EM) to fully understand the molecular mechanisms of R2TP/PFDL and to bring us a step closer to designing strategies to interfere with PIKK assembly and activation.
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