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Postdoctoral Position to be advertised soon

There is one postdoctoral position available in Leicester in the AMBER call, to work on one of the below projects. You are encouraged to get in touch with one of the supervisors for the project you are interested in before applying. The call is not yet open, but here is a list of the projects and get in touch with the advertising supervisors:

Project: Fine-tuning the engine of energy transfer in biology: proton-coupled electron transfer interrogated using advanced ultrafast spectroscopy and computational approaches

Philip Ash, James Pickering, Patricia Rodriguez-Macia

Coordinated movements of two quantum particles, protons (H⁺) and electrons, are crucial to vital energy conversion processes in biology. Highly-controlled biological proton-coupled electron transfer (PCET) reactions enable activation of H₂ and CO at high rates, and conversion of CO₂ into value-added organic building blocks. In order to exploit the lessons of Nature and develop a new era of cheap and sustainable catalysts for energy conversion, we need to achieve a detailed and dynamic understanding of the underpinning biological PCET. Led by a multidisciplinary team, this project exploits a unique suite of ultrafast spectroscopic imaging, structural, and electrochemical approaches to target biological PCET and rational design of future green catalysts.

This exciting multidisciplinary project utilizes a wide range of cutting-edge methods to target the heart of biological energy transfer – the coupled (or not) motion of protons and electrons – working with a dynamic research team that will provide opportunities for networking and travel to international facilities.

Project: Deciphering the interplay between chromatin and double-stranded DNA repair complexes

Amanda Chaplin, Thomas Schalch, Patrick Calsou, Paul Sabatier

Non-homologous end joining (NHEJ) is a critical DNA repair mechanism that rejoins double-stranded DNA breaks, essential for cell survival and genome stability. While the core components of NHEJ are well characterized, their molecular interplay within the chromatin environment remains poorly understood. This project aims to uncover these mechanisms using cutting-edge cryo-electron microscopy (cryo-EM), with direct implications for cancer therapy. Despite its fundamental importance in DNA repair and its established role as a therapeutic target in cancer treatment, several key questions remain unanswered:

1. How does DNA-PK recognize and interact with nucleosomes near DNA break sites?
2. What structural changes occur in chromatin during NHEJ initiation?
3. How do chromatin remodelers and modifying complexes coordinate with the NHEJ machinery?

This project combines cutting-edge structural biology with fundamental questions in genome stability, promising both mechanistic insights and therapeutic applications. Understanding how NHEJ operates in its native chromatin environment will fill a crucial knowledge gap in DNA repair biology while potentially enabling new therapeutic strategies in cancer treatment.

Project: Structural investigation of the intrinsically disordered regions of the RNA binding protein Sam68

Cyril Dominguez, Marie Skepo

Intrinsically disordered regions (IDRs) or protein play crucial roles in almost all cellular functions. Still, the molecular mechanisms that govern their functions remains largely unknown.

Sam68 is a RNA binding protein that contains a folded RNA binding domain flanked by N-terminal and a C-terminal IDRs. The Nter and Cter IDRs of Sam68 have the ability to bind RNA specifically and phosphorylation of a single threonine residue inhibits their RNA binding ability and consequently the cellular functions on the protein.

This raises three important questions:

1. How does an unstructured protein region specifically bind unstructured RNA?
2. How does phosphorylation of a single amino acid affect the RNA binding properties of the protein?
3. How does full-length Sam68 specifically recognize its RNA targets?

We will answer these questions by combining structural and biophysical methods (NMR, FCS, FRET, SAXS, nano-tweezers, AFM) with molecular dynamics.

Project: Pin-ing it down: Cooperative Protein Destabilisation via Covalent Modification

Richard Doveston, Gareth Hall, Marie Skepo, Zoe Fischer

The human parvulin prolyl isomerase Pin1 catalyses the cis/trans isomerization of over 200 protein substrates containing phosphorylated serine-proline (pSer-Pro) and threonine-proline (pThr-Pro) motifs. This regulates the activity of these substrates within the cell. Dysregulation of Pin1 levels is strongly associated with the activation of multiple cancer-related pathways. Consequently, the development of therapeutic strategies targeting Pin1 has gained significant interest. Despite efforts to design traditional small-molecule inhibitors that target Pin1’s catalytic domain, none have emerged as potential drug candidates. Thus, there is a need to develop alternative approaches for targeting Pin1. We have shown how Pin1 substrate recognition and enzymatic activity can be controlled by combinatorial phosphorylation (Doveston et al., Protein Science, 2024). Inspired by this, we have also discovered a novel approach for combinatorial dual-ligand covalent modification of Pin1.We aim to determine the molecular mechanism of dual ligand Pin1 destabilisation and use that understanding to optimise the molecular crowbar effect in terms of potency and selectivity. This will deliver the next generation of Pin1 targeting drugs which are urgently needed for the further validation of Pin1 as a therapeutic target in cancer. Furthermore, we envisage that this strategy can be applied to numerous other proteins. 

Project: Development of novel allosteric inhibitors to sensitise cancer cells to death

Joanna Fox, Richard Doveston, Cyril Dominguez

Apoptotic resistance is a hallmark of cancer cells and a major barrier to the efficacy of many chemotherapeutic drugs, which rely on mitochondrial apoptosis for cell killing. BMX is a tyrosine kinase, which is over-expressed in numerous important cancers and cancer derived cell lines, where it simultaneously promotes proliferation and inhibits apoptosis. Using genetic methods, we have shown that BMX over-expression in model cell lines raised the apoptotic threshold for BAK activation and increased resistance to cell killing. Using In silico Fragment-based screening 3.4 million lead-like compounds were screened for specificity for BMX in comparison to the closely related kinase BTK. From this, 96 structurally diverse ‘hits’ were selected for further investigation. From these ‘in-silico hits’ we have identified a molecule that reproducibly inhibits BMX kinase activity in vitro but does not bind to the kinase pocket.

This project aims to develop this allosteric ‘hit’ to stabilise and lock BMX in its inactive conformation.

Project: Defining how reactive metabolites regulate the protein cysteinome

Richard Hopkinson, Steve Bull, Chris Switzer,

The biology of reactive metabolites (RMs) such as aldehydes and reactive oxygen and sulfur species is undetermined at the molecular level. This is largely because RMs are difficult to work with (reactive, small, unstable, volatile) and can exhibit different effects at different concentrations. To fully define the biology of RMs, a holistic multidisciplinary approach is required that combines chemical biology tools with cellular methods.

Cysteine is redox-sensitive and is the most nucleophilic amino acid under physiological conditions. It is therefore the most likely amino acid on proteins to undergo reactions with RMs. There are a growing number of reported RM-cysteine reactions on proteins, with many reported to induce functional changes. Many cysteine modifications are also reported to occur in disease and ageing. Understanding how RMs react with and affect the functions of cysteine-containing proteins is therefore of interest to basic science and biomedically focused research. We will use bespoke RM-modulating chemical tools and imaging/detection methods to identify, characterise and phenotypically analyse RM reactions on cellular protein cysteines.

Project: Structural studies on nanomachines driving UV-induced DNA transfer in archaea

Abhinav Koyamangalath Vadakkepat, Amanda Chaplin

Horizontal gene transfer (HGT) and genetic recombination are key drivers of genome plasticity and adaptability in microbial populations. In bacteria, conjugative plasmid transfer significantly contributes to the spread of antimicrobial resistance (AMR). Conversely, archaea such as Sulfolobaceae have evolved mechanisms that couple HGT with DNA repair, thereby promoting survival in extreme environments^1,2. Following UV-induced stress, Sulfolobus acidocaldarius induces pilus formation, facilitating cell aggregation and the transfer of single-stranded DNA (ssDNA) via the Ced transporter³, which imports genomic DNA for double-strand break repair.

This project aims to dissect the molecular basis of Ced-mediated DNA import and the preceding processing of double-stranded DNA by NurA-HerA complexes. Using cryo-electron microscopy (cryo-EM), biochemical characterisation, single-molecule analysis, and live-cell imaging, this study seeks to provide a comprehensive understanding of archaeal DNA transfer and its evolutionary parallels with bacterial conjugation.

AMBER

A consortium including LISCB has been awarded major funding from the EU Marie SkÅ‚odowska-Curie (MSCA) COFUND scheme for a project entitled Advanced Multiscale Biological imaging using European Research infrastructures (AMBER). AMBER will fund a five-year postdoctoral programme for 47 postdoctoral researchers to address key needs for biological imaging of fundamental importance to human health.

The consortium has six core partners:

• Lund University/MAX IV
• European Spallation Source, Sweden
• The European Molecular Biology Laboratory
• Institut Laue-Langevin, France
• The International Institute of Molecular Mechanisms and Machines, Poland
• Leicester Institute of Structural and Chemical Biology, United Kingdom

PhD opportunities

Funding

External funding for PhD positions is available through the schemes below. Students who are interested in doing doctoral research at the Institute are encouraged to apply to these and get in touch with Dr Tennie Videler (hv33@le.ac.uk) beforehand. We can support you to put in the strongest possible application as these are very competitive.

BBSRC MIBTP

 is a BBSRC-funded Doctoral Training Partnership (DTP) between the University of Warwick, the University of Birmingham, the Â鶹ÊÓƵ, Aston University and Harper Adams University with an emphasis on interdisciplinarity (4 years).

The projects below are looking for doctoral candidates. If you apply, consider asking for support from the prospective supervisors and Tennie (hv33@le.ac.uk) to put in the best possible application. Recruitment is now closed.

MRC Advanced Inter-disciplinary Models (AIM)

 is a 3.5 year Doctoral Training Programme funded by the MRC between the Universities of Birmingham, Nottingham, and Leicester. Doctoral students benefit from a diverse range of skills within the cohort, stimulating students to think ‘outside the box’ and perform innovative, world-leading research. The partner universities contribute project ideas, which prospective doctoral students choose from. Recruitment is now closed.

Doctoral Training Programme

To introduce PhD students to the full extent of technical capabilities and resources in the Institute of Structural and Chemical Biology, we have established a doctoral training programme for each new PhD cohort. By following this training element in the research degree, we hope for students to develop independence and a critical way of thinking, and become equipped with technical expertise beyond the specific tools and method used in their projects. The first year of the training programme is focussed on building skills across a broad range of techniques in structural and chemical biology. Subsequent years of the training programme are focussed on transferable skills, building independence and preparation for post-degree careers.

Job opportunities

We are always looking to explore options of gaining fantastic new colleagues. Please get in touch with Tennie (hv33@le.ac.uk) or individual academics to discuss.

Why the Institute of Structural and Chemical Biology?

Profit from the informed teaching fuelled by the cutting-edge research at the Institute

• Access to the world class facilities at the Institute as well as the facilities at the University such as the award-winning David Wilson Library
• Members within the Institute will also benefit from the expertise and support from the Departments of Chemistry, Molecular and Cell  Biology and Respiratory Sciences.