# Structure and functional mechanisms of molecular chaperones and protein kinases

> **NIH NIH R35** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $764,284

## Abstract

PROJECT SUMMARY
Our lab works on two main directions: first, the determination of the structural and dynamic basis for
the function and assembly of large protein machineries; and second, the determination of the role of
internal protein dynamics in regulating protein activity and allosteric interactions. We propose to use
NMR spectroscopy, together with other biochemical and biophysical techniques, to determine at the
atomic resolution the mechanisms underpinning the function of two important protein families:
molecular chaperones and protein kinases.
Molecular chaperones are central to maintaining a functional proteome in the cell by rescuing non-
native proteins from aggregation and misfolding and assisting with their folding. Our lab reported the
first ever high resolution structures of molecular chaperones in complex with unfolded proteins. We
will determine the structures of important chaperones such as the Hsp40, Hsp70 and Hsp90 in
complex with client proteins. We wish to address how different chaperones engage non-native
proteins and how distinct chaperone architectures may alter activity.
Src and BRAF hold a prominent place among the over 500 protein kinases encoded by the human
genome. Src is the archetypical kinase of the ~30 cytoplasmic tyrosine kinases, half of which (Src,
Frk, Abl, Tec and Csk families) share the same core domain architecture consisting of an SH3, SH2
and kinase domain. As such, Src has served as the prototype for understanding how allosteric
interactions regulate the activity of kinases. BRAF is a member of RAF kinases and is a part of the
ERK signaling pathway, one of the most important and best studied signaling pathways in human
cancers. The BRAF gene is mutated in approximately 8% of human tumors with substitutions in the
A-loop, the P-loop and the DFG motif reported to give rise to a hyperactive kinase. We will use NMR
spectroscopy to characterize transiently populated conformational states, with the goal of uncovering
novel regulatory mechanisms in the human kinome.

## Key facts

- **NIH application ID:** 10770400
- **Project number:** 5R35GM122462-08
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** CHARALAMPOS KALODIMOS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $764,284
- **Award type:** 5
- **Project period:** 2017-05-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770400

## Citation

> US National Institutes of Health, RePORTER application 10770400, Structure and functional mechanisms of molecular chaperones and protein kinases (5R35GM122462-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10770400. Licensed CC0.

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