The major biological focus of the Enchev lab is the molecular mechanism and regulation of ubiquitin signalling. Ubiquitination is a versatile signalling mechanism in eukaryotes, which regulates critical aspects of cellular metabolism under homeostatic and stress conditions. Cullin-RING E3 ligases (CRLs) comprise nearly half of all cellular ubiquitin ligases and account for nearly 20% of all cellular ubiquitination. The assembly and activity of CRLs are regulated by only a few factors and despite a wealth of biochemical and cellular data, many mechanistic questions remain open due to the scarcity of structural information of functionally important states. Recently, many CRL family members have attracted attention from the biotech and pharmaceutical industries due to their utility as effectors of chemically induced proximity degraders of otherwise undruggable proteins. Such drug like probes bring together E3 ligases with non-native substrates and thus enable ubiquitin transfer. Presently they are found serendipitously and the overarching rules of their mechanisms of action, as well as failure modes, are not well understood. A major technical limitation is that the basic toolkit of structure-based drug design is of limited utility due to the rapid and conformationally dynamic nature of poly-ubiquitination. Hence, we are developing and applying novel techniques to integrate time-resolved cryo-EM and single particle analysis as well machine learning techniques for data processing to enable new research avenues and insights.
The purpose of this role is to perform biochemical reconstitutions as well as biophysical and structural studies relating to poly-ubiquitination induced by molecular glue probes.
In this project, some of the specific aims include but are not limited to:
- In vitro biochemical reconstitution of relevant ubiquitin E3-target complexes
- Development and execution of quantitative binding and activity assays, suitable for high-throughput screening
- Structural studies of above complexes
- Comparative structural analysis of the conformational landscapes of complexes induced by molecular glue probes of varying potency
The postholder will be responsible for:
- Experimental design and execution
- Data documentation and regular internal presentations
- Dissemination of scientific results through scientific conferences and publications
Postdoctoral Training Fellows will be expected to creatively lead their own project within the programme in addition to actively contributing to other projects within the programme on a collaborative basis, they may guide PhD students in their research. The ability to work in a team is essential.
This is a unique opportunity to be part of a truly multi-disciplinary research programme, which will train the next-generation of scientific leaders, equipped to succeed both in academia and in industry as part of the collaboration there will be the opportunity to learn more about drug discovery through active involvement in AZ bespoke training courses. You will work with highly experienced colleagues and collaborators in an institute that values discovery without boundaries.
Key experience and competencies
- PhD in Biochemistry (and related fields) or in the final stages of PhD submission
- Theoretical and technical expertise in at least two of the following areas: in vitro protein biochemistry, quantitative biophysical assays, cryo-electron microscopy and single particle analysis
- Track record of writing papers as evidenced by publications or submitted manuscripts in peer-reviewed journals
- Ability to work independently and as part of a team
- Evidence of data presentation at scientific meetings
- Experience with setting up biophysical assays, e.g. FRET
- Experience in biochemistry of ubiquitin signaling and protein degradation
- Experience in high resolution structure determination and model building
- Experience in modelling of protein dynamics
- Experience in high throughput screening
At the Crick, we conduct research at the forefront of biomedical research. We combine rigour with an open and collaborative culture, and are outward-looking, reflecting our status as a partnership of six organisations aiming to pool knowledge, ideas and resources.
We have a wide research portfolio with no divisions or departments, bringing biomedical researchers together with clinicians, physical scientists and applied scientists from our pharmaceutical partners.
We aim to attract the most talented researchers and support them to tackle innovative research questions. Our science technology platforms provide our researchers with access to state-of-the-art technology and expertise.
We provide an excellent learning environment with dedicated education programmes in public engagement with science, education and personal development, and a postdoc training programme that prepares scientists for leadership roles in science.
If you are interested in applying for this role, please apply via our website.
The closing date for applications is 19 May 2023 23:59.
All offers of employment are subject to successful security screening and continuous eligibility to work in the United Kingdom.
If you require a visa to work in the UK we will help support your application should you be successful
Find out what benefits the Crick has to offer:
For more information on our great pay and benefits package please click here: https://www.crick.ac.uk/careers-and-study/life-at-the-crick/pay-and-benefits
Equality, Diversity & Inclusion:
We welcome applications from all backgrounds. We are committed to providing equal employment opportunities, regardless of ethnicity, nationality, gender, sexual orientation, gender identity, religion, pregnancy, age, disability, or civil partnership, marital or family status. We particularly welcome applications from people who are Minority Ethnic as they are currently underrepresented in the Crick at this level.
Diversity is essential to excellence in scientific endeavour. It increases breadth and perspective, leading to more innovation and creativity. We want the Crick to be a place where everyone feels valued and where diversity is celebrated and seen as part of the foundation for our Institute’s success.
The Crick is committed to creating equality of opportunity and promoting diversity and inclusivity. We all share in the responsibility to actively promote dignity, respect, inclusivity and equal treatment and it is our aim to ensure that these principles are reflected and implemented in all strategies, policies and practices.
Read more on our website: https://www.crick.ac.uk/careers-and-study/life-at-the-crick/equality-diversity-and-inclusion