Institute for Structural and Chemical Biology

Research opportunities

AMBER- Postdoctoral opportunities

Two positions are now open. Closing date for application 1 July 2026. There are 6 projects to choose from- please contact one of the academics mentioned in bold for more details and to discuss support for your application:

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

Richard Doveston and Gareth Hall 

Pin1 is a prolyl isomerase enzyme that catalyses the cis/trans isomerization of proline residues in over 200 protein substrates. 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 inhibiting Pin1.

The aim of this project is to define and exploit the mechanisms behind recently discovered covalent ligands that work together as ‘molecular crowbars’ to ‘pin’ Pin1 into an inactive state.  This leads to Pin1 degradation in the cell. We will use an interdisciplinary approach in which mechanistic studies inform ligand design and synthesis.

Molecular crowbar mechanism: Using protein NMR in combination with biophysical analyses, including FRET-based biosensors, we will define the molecular events that lead to Pin1 destabilization. These experimental data sets will be combined with computational analysis (with Marie Skepö, Lund) to understand the physics behind induced protein disorder. Ultimately, we will create a mechanistic model for how disorder of Pin1 is induced that will inform ligand design.

Ligand development: The structural data will be used to design and synthesise ‘bitopic’ ligands that contain two electrophilic sites. These ligands will mimic the dual-ligand covalent modification effect in a single drug-like molecule. In principle, this bivalent binding effect should lead to much greater potency (due to higher affinity), and selectivity because it must recognise two binding sites simultaneously. Ultimately, this work will deliver new small molecule inhibitors of Pin1 that will great advance drug development and fundamental understanding.

  1. Scientific Reports, 2025, 10.1038/s41598-025-89342-0
  2. Protein Science, 2024, 10.1002/pro.5138
  3. Proc. Natl. Acad. Sci., 2024, 10.1073/pnas.2403330121

Structural investigation of the intrinsically disordered regions of the RNA binding protein Sam68: implication for RNA binding and phosphorylation 

Cyril Dominguez, Andrew Hudson and 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. In recent years, classical structural and biophysical techniques (NMR, FRET, SAXS, ...) have been combined with molecular dynamics simulations to generate structural ensembles and derive the mechanisms of their functions.

Sam68 is a typical RNA binding protein that contains a classical folded RNA binding domain flanked by N-terminal and a C-terminal IDRs. While these IDRs have been shown to be crucial for the function of Sam68 and are targets of multiple post-translational modifications, the molecular mechanisms of their contribution remains unknown.

Our published (Malki et al, NAR, 2022) and preliminary data clearly show that the Nter and Cter IDRs of Sam68 have the ability to bind RNA specifically and that 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 bind specifically an unstructured RNA? What are the molecular basis for the specificity?
  2. How does phosphorylation of a single-amino acid have such an impact on the RNA binding properties of the protein?
  3. How does full-length Sam68 recognize specifically its RNA targets

We will answer these questions by combining the team expertise in structural and biophysical methods (NMR, FCS, FRET, SAXS) with molecular dynamics to decipher the structural properties of these regions.

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

Amanda Chaplin and Thomas Schalch

Non-homologous end joining (NHEJ) is a major DNA repair pathway that resolves double-strand breaks and preserves genome stability. While the core NHEJ machinery is well characterised, its structural organisation within chromatin remains poorly understood. This project aims to define how NHEJ operates in the chromatin environment using state-of-the-art cryo-electron microscopy (cryo-EM), with important implications for cancer therapy.

NHEJ begins when the Ku70/80 heterodimer recognises DNA breaks and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming the DNA-PK holoenzyme. DNA-PK activates downstream signalling through phosphorylation of histone H2AX and other substrates, ultimately promoting DNA end ligation. However, these events occur within chromatin, where DNA is wrapped around histone octamers and organised into higher-order structures.

We will address three key questions: (1) how does DNA-PK engage nucleosomes near DNA breaks? (2) What structural changes occur in chromatin during NHEJ DNA-repair, and (3) how do chromatin-modifying complexes coordinate with NHEJ factors? Building on our recent cryo-EM structures of DNA-PK–nucleosome complexes, we will reconstitute DNA-PK on nucleosomal substrates to capture DNA-PK during phosphorylation of H2AX nucleosomes and determine structures of DNA-PK assemblies with chromatin remodellers.

Structural insights will be validated through structure-guided mutagenesis and cellular assays measuring kinase activity, recruitment of fluorescently tagged repair proteins to laser-induced DNA damage, and DNA repair efficiency in collaboration with the DNA damage response team at IPBS in Toulouse, France.

These studies will reveal the molecular mechanism of NHEJ in chromatin and identify new interfaces for therapeutic targeting.

References

“Cryo-EM structures of NHEJ assemblies with nucleosomes”. Hall C, Frit, P, Kefala-Stavridi A, Pelletier, A, Hardwick SW, Bilyard, M, Amin, H, Oliveira, TMD, Tariq, A, Zahid, S, Chirgadze DY, Balasubramanian, S, Meek, K, Calsou, P, Schalch, T, Chaplin AK. 2025. Nature Comms

“Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ”. Frit, P, Amin, H, Zahid, S, Barboule, N, Hall, C, Matharu G, Hardwick SW, Chauvat, J, Britton, S, Chirgadze DY, Ropars, V, Charbonnier JB, Calsou, P, Chaplin AK. 2025. Nature Comms.

Cryo-EM of NHEJ super complexes reveal new insights into DNA repair”. Chaplin AK, Hardwick SW, Kefala Stavridi A, Liang S, Chirgadze, DY, Blundell, TL. 2021.– Molecular Cell. 16. 3400-3409.

Structural and Functional Characterisation of the RexAB-mediated Abortive Infection Bacteriophage Defence System

Abhinav Koyamangalath Vadakkepat and Amanda Chaplin

Antimicrobial resistance (AMR) is responsible for approximately one million deaths each year and continues to undermine the efficacy of conventional antibiotics. While bacteriophage therapy is experiencing renewed interest as an alternative antimicrobial strategy, its success is fundamentally limited by bacterial antiviral defence systems that actively restrict phage replication.

This project will investigate the RexA–RexB abortive infection system of bacteriophage in Escherichia coli, a historically important but mechanistically unresolved Abi model. Rex-mediated defence is triggered during phage superinfection leading to irreversible energetic failure and termination of viral replication. RexA may function as a sensor–regulator detecting phage-induced DNA perturbations. Activated RexA is proposed to engage the membrane protein RexB, triggering membrane depolarisation and catastrophic bioenergetic collapse.

The overarching aim of this project is to establish a unified structural and mechanistic framework for RexAB-mediated abortive infection. Specifically, the project will:

(1) define the DNA substrates and repair-associated signals that activate RexA

(2) characterise the conformational transitions underpinning RexA activation and regulatory integration

(3) determine how RexA activation is coupled to RexB-dependent membrane depolarisation

By combining cryo-EM, bacterial genetics, quantitative phage burst assays, biochemistry, electrophysiology, and single-cell bioenergetic analyses, this research will link atomic-level structure to cellular outcome. The findings will establish general principles of energy-coupled antiviral decision-making and inform strategies to overcome bacterial defence barriers in phage therapy, directly addressing AMR priorities.

Mechanism of chromatin folding by cohesion

Daniel Panne and Andrew Hudson

It is becoming increasingly apparent that dynamic and spatial organisation of the genome is key for the control of DNA-based processes including gene expression, recombination, repair, replication and mitosis. In eukaryotes, genomic DNA is wrapped around histone octamers that form nucleosomes, which assemble into chromatin fibres. These are epigenetically controlled by histone modifying enzymes, but chromatin fibres are also spatially organised through the formation of loops, which can span hundreds of kilobases in length. Key to the epigenetic control of chromatin structure is ’reading’ and writing’ of reversible histone acetylation while spatial control is mediated by the cohesin complex. Cohesin organises the interphase genome by reeling DNA into loops which grow in size until loop extrusion is stopped by CTCF or until cohesin is removed from DNA by the cohesin release factor WAPL. We propose to address the following key questions:

  1. How does cohesion extrude chromatin fibres?
  2. How do cohesion-mediated loop extrusion and chromatin states regulate each other?

We will reconstitute DNA loop extrusion in single-molecule imaging experiments both on naked DNA and on chromatin fibres. We will visualize the impact of acetylation-dependent compaction of chromatin on loop extrusion using the newly acquired LUMICKS C-trap optical tweezers instrument. The proposed project will address fundamental questions in molecular biology at the mechanistic level. The expected results will be relevant for understanding chromatin biology, genome architecture and regulation and for revealing how SMC complexes control higher-order chromatin structure. As Cohesin and its subunits are among the most frequently mutated genes found in human cancers and are the cause of cohesinopathies and chromosomal disorders (trisomy) and spontaneous abortion, the research proposed here may also provide insight into the ecology of these disorders.

Visualizing PROTAC Engagement in HDAC–Corepressor–E3 Ligase Assemblies by Cryo‑EM to Enable Structure‑Guided Drug Discovery

James Hodgkinson, John Schwabe and Emma Hesketh

This project aims to use cryo‑electron microscopy to visualize proteolysis‑targeting chimera (PROTAC) molecules and the molecular interactions they induce between class I HDAC corepressor complexes and E3 ligases. Class I HDACs are validated therapeutic targets across multiple disease areas and exist within several biologically distinct corepressor complexes.1 PROTACs degrade proteins by recruiting an E3-ligase and ‘hijacking’ the ubiquitin proteasome pathway, with over 20 PROTACs currently in clinical trials.2 The interdisciplinary team has experience in the design and synthesis of class I HDAC targeting PROTACs3 and the structural biology of class I HDAC corepressor complexes.4 By resolving the ternary assemblies formed between the PROTAC, the HDAC corepressor complex, and the E3 ligase, we will gain structural insights that can directly inform next‑generation PROTAC design to improve selectivity and potency. The ability to rationally design PROTACs to bias recruitment toward specific HDAC corepressor complexes would represent a major advance for the field. This project therefore has the potential to establish a new paradigm in the selective modulation of HDAC function.

The project will involve the expression and purification of class I HDAC corepressor complexes, together with E3‑ligase assemblies. These purified complexes will be examined using Cryo-EM in the presence of newly developed class I HDAC‑targeting PROTACs. The resulting structural insights will directly inform the rational design of next‑generation PROTACs. This project is ideally suited to candidates interested in developing advanced skills in chemical biology and structural biology, offering hands‑on experience at the interface of molecular mechanism and rational PROTAC design.

References

1. Millard, C.J., Watson, P.J., Fairall, L. and Schwabe, J.W., 2017. Targeting class I histone deacetylases in a “complex” environment. Trends in pharmacological sciences, 38(4), pp.363-377.

2. Zhong, G., Chang, X., Xie, W. and Zhou, X., 2024. Targeted protein degradation: advances in drug discovery and clinical practice. Signal transduction and targeted therapy, 9(1), p.308.

3. Smalley, J.P., Baker, I.M., Pytel, W.A., Lin, L.Y., Bowman, K.J., Schwabe, J.W., Cowley, S.M. and Hodgkinson, J.T., 2022. Optimization of class I histone deacetylase PROTACs reveals that HDAC1/2 degradation is critical to induce apoptosis and cell arrest in cancer cells. Journal of medicinal chemistry, 65(7), pp.5642-5659.

4. Watson, P.J., Fairall, L., Santos, G.M. and Schwabe, J.W., 2012. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature, 481(7381), pp.335-340.

Amber

A consortium including LISCB has been awarded major funding from the EU Marie Skłodowska-Curie (MSCA) COFUND scheme for a project entitled Advanced Multiscale Biological imaging using European Research infrastructures (AMBER).Amber logo, frog on orange background

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

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

MIBTP is a BBSRC-funded Doctoral Training Partnership (DTP) between the University of Warwick, the University of Birmingham, the University of Leicester, Aston University and Harper Adams University with an emphasis on interdisciplinarity (4 years). Recruitment is currently closed.

MRC Advanced Inter-disciplinary Models (AIM)

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

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