Postdoctoral Fellow

Postdoctoral Fellow – Cherepanov Lab

Reports to: Peter Cherepanov, Group Leader

Contact term: This is a full-time, fixed term (4 year) position on Crick terms and conditions of employment.

Project summary

The insertion of a DNA copy of the viral genome into a host cell’s chromosome is an essential step in retroviral replication. The virus-derived enzyme integrase (IN) is responsible for the key catalytic events involved in this process. HIV-1 integrase is a critical target for the development of antiviral drugs, with IN strand transfer inhibitors being in clinical use since 2007. In addition to its well-established enzymatic function, HIV-1 IN also plays a role in viral morphogenesis. Disruption of viral maturation—either through mutations in IN or treatment with allosteric inhibitors—leads to the formation of aberrant, non-infectious HIV-1 particles with genomic RNA located outside the capsid core. However, the structural bases of the IN-RNA interaction and for the role of IN in viral maturating remain unknown.

This project will focus on the structural organization of the HIV-1 integration machinery. The successful candidate will study native pre-integration complexes isolated from infected cells using a range of biophysical and analytical techniques. Another exciting aspect of this project will involve dissecting the interactions between retroviral IN and RNA, and exploring how integrase facilitates the packaging of the viral RNA genome into mature cores. Research goals will be established in collaboration with the principal investigator.

The Research Group

The laboratory is dedicated to structural studies of viral replication and host-pathogen interactions. The group’s research efforts aim to understand the process of retroviral DNA integration, the roles of retroviral IN outside its canonical functions, and the mechanisms behind HIV-1 restriction factors, such as SERINC5. The laboratory also collaborates extensively with our groups within the Institute and with international partners.

The main techniques employed in the lab are cryo-electron microscopy (cryo-EM) and X-ray crystallography, supported by the Institute’s state-of-the-art facilities. The Cryo-EM facility provides access to two Titan Krios 300-kV microscopes, each equipped with Falcon IV detectors, along with Talos Arctica and Glacios 200-kV instruments, and two 120-kV TEM screening microscopes. Cryo-EM data processing is conducted using an in-house CPU/GPU cluster.

The Crystallography facility is equipped with cutting-edge instrumentation, including two Rock Imager 1000s for high-throughput crystallization screening and optimization at two temperatures, two Formulator-16s, and an X-ray suite featuring a Bruker D8 Venture X-ray diffraction system. The system is powered by an Excillum liquid MetalJet X-ray generator coupled with the latest photon-counting detector, producing a highly intense 75-μm beam. This setup allows the testing of small crystal systems in-house, along with a fully automated crystal plate adapter capable of examining crystals in situ.

A recent review on the topic and selected publications from the laboratory:

Maertens GN, Engelman AN, Cherepanov P. (2022) Review: Structure and function of retroviral integrase. Nat. Rev. Microbiol. 20, 20-34. doi: 10.1038/s41579-021-00586-9.

Singer MR, et al. (2023) The drug-Induced interface that drives HIV-1 integrase hypermultimerization and loss of function. mBio 14, e0356022; doi: 10.1128/mbio.03560-22.

Baggen J, et al. (2023) TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell. 186, 3427-3442.e22. doi: 10.1016/j.cell.2023.06.005.

Ballandras-Colas A, et al. (2022) Multivalent interactions essential for lentiviral integrase function. Nat. Commun. 13, 2416. doi: 10.1038/s41467-022-29928-8.

Rosa, A., et al. (2021). SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity. Sci. Adv. 7, eabg7607; doi: 10.1126/sciadv.abg7607.

Pye, V.E., et al. (2020). A bipartite structural organization defines the SERINC family of HIV-1 restriction factors. Nat. Struct. Mol. Biol. 27, 78-83; doi: 10.1038/s41594-019-0357-0

Cook, N.J., et al. (2020). Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806-810; doi: 10.1126/science.aay4919.

Lesbats, P., et al. (2017). Structural basis for spumavirus Gag tethering to chromatin. Proc. Natl. Acad. Sci. USA 114, 5509-5514. doi: 10.1073/pnas.1621159114.

Ballandras-Colas, A., et al. (2017). A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93-95. doi: 10.1126/science.aah7002.

Maskell, D.P., et al. (2015). Structural basis for retroviral integration into nucleosomes. Nature 523, 366-369. doi: 10.1038/nature14495.

Key responsibilities

Postdoctoral Training Fellows are expected to lead their own projects, contribute to other projects on a collaborative basis (both in the lab and with external collaborators) and help guide PhD and MSc students in their research.

The responsibilities include but are not limited to:

• Investigating research questions and developing specific research project(s) under guidance from the group leader.

• Providing specialist advice and guidance, sharing knowledge and expertise for the benefit of others.

• Providing significant contribution to the production of research papers for publication, presenting findings to group members and other internal audiences.

• Presenting work externally at international meetings.

• Authoring papers under guidance from group leader.

• Following Postdoctoral Training programme.

• Developing academic independence.

• Improving established protocols and/or develops new protocols.

• May be required to guide others.

Key experience and competencies

The post holder should embody and demonstrate our core Crick values: bold, open, collegial, in addition to the following:

Essential

• PhD (or in the final stages of PhD thesis submission) in biomedical sciences, biophysics, or medicinal chemistry.

• Good knowledge of and experience in protein chemistry, recombinant protein production and purification.

• Expertise in recombinant protein expression and purification, using variety of host systems.

• Technical expertise in cryo-EM, including extensive hands-on experience if image processing, model building and validation.

• Track record of writing papers as evidenced by publications (or submitted manuscripts) in refereed journals.

• Evidence of data presentation at scientific meetings.

• Understanding of and experience in experimental design.

• Ability to work independently while productively interacting within a group.

• Independent thinking and drive to succeed.

Desirable

• Experience with cell and viral culture.

• Experience in in vitro nucleosome/chromatin assembly.

• Experience in recombinant protein production in cell culture.

About Us

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 programme that prepares scientists for leadership roles in science.

• If you are interested in applying for this role, please apply via our website.

• 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