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Understanding mechanisms of small-molecule inhibition of the mitochondrial chaperonin HSPD1

Project Description

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer. Treatment options are insufficient, survival rates are low. We have discovered that the energy metabolism of patient-derived GBM cells is crucially dependent on HSPD1, a mitochondrial chaperonin that is responsible for the the correct folding of various metabolic enzymes in the mitochondrial matrix. In addition, we have identified a small molecule – KHS101 – that selectively kills GBM cells by inhibition of HSPD1 (Polson et al., Sci. Transl. Med. 2018). Our pilot data suggest that KHS101 inhibits HSPD1 through a novel mechanism, preventing formation of the complex between HSPD1 and its co-chaperonin HSPE1. In this interdisciplinary project, you will gain structural insights into the mode-of-action of KHS101 and use these to develop improved HSPD1 inhibitors. You will use intact protein mass spectrometry and peptide mapping to validate the proposed KHS101 binding site of HSPD1, determine a structure of HSPD1 bound to KHS101 (by cryo-electron microscopy or crystallography), and develop new KHS101 analogues for testing in established biochemical and cellular assays. The findings will underpin future structure-based cancer drug discovery programmes.

Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2020:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference and research funding

At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.

EU candidates require 3 years of UK residency to receive full studentship

Not all projects will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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How good is research at University of Leeds in Chemistry?

FTE Category A staff submitted: 34.40

Research output data provided by the Research Excellence Framework (REF)

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