The chaperone cycle of fibroblast growth factor receptor kinases in molecular detail

Award Number
Status / Stage
1 June 2022 -
31 May 2025
Duration (calculated)
02 years 11 months
Funding Amount
Funder/Grant study page
Contracted Centre
University of Leeds
Principal Investigator
Professor Alexander Breeze
PI Contact
WHO Catergories
Understanding Underlying Disease
Disease Type
Dementia (Unspecified)

CPEC Review Info
Reference ID744
ResearcherReside Team


Award NumberBB/W008017/1
Status / StageActive
Start Date20220601
End Date20250531
Duration (calculated) 02 years 11 months
Funder/Grant study pageBBSRC UKRI
Contracted CentreUniversity of Leeds
Funding Amount£618,079.00


In this 3-year project grant we will combine and integrate insights from an array of advanced structural techniques, including cryo-EM, H-D exchange- and ion mobility-MS, and methyl-resolved and paramagnetic NMR, to effect a step change in our understanding of how FGFRs (hence RTKs more broadly) interact with the Cdc37-HSP90 chaperone system. Over a number of years we have established in our labs the means to generate heterotrimeric/tetrameric complexes that represent defined points on the kinase-co-chaperone-chaperone interaction cycle through in vitro reconstitution of individually expressed and purified components carrying functional mutations, e.g. E47A and D93N ATP-binding/hydrolysis HSP90 mutants, I538F DFG-latch mutant FGFR3, thus overcoming what can often be a major limiting factor in structurally-based projects. Our methyl-resolved NMR platform will enable us to define the rules for discrimination by Cdc37 between kinase variants on the strong-weak client continuum, and how these features are selected for presentation to HSP90. Furthermore, we will be able to probe the effect of HSP90 inhibitors such as PU-H71 on the full complex structure and dynamics, and answer the question of whether there is obligate order and homogeneity in the assembly of the kinase-co-chaperone-chaperone complexes.