Senior Laboratory Research Scientist - Structural Biochemist

Senior Laboratory Research Scientist - Structural Biochemist

Visual Biochemistry lab, AZ-Crick-Alliance

Reporting to: Radoslav I. Enchev, Group Leader

Contract term: This is a full-time, fixed term (3 year) position on Crick terms and conditions of employment.

The AZ-Crick Alliance

AstraZeneca and the Francis Crick Institute have established a productive research collaboration, supporting discovery biology research and early translational projects since December 2016. This has brought together the combined knowledge and capability of Crick and AZ scientists to work on areas of technology development, mechanistic understanding and novel target validation.

The Team

The Cryo-EM team within AstraZeneca’s Discovery Sciences has extensive expertise in the application of the technique in the design of novel therapeutics across multiple modalities and therapeutic areas. In addition, we have a strong interest in the application of emerging technologies within the technique to inform drug discovery on difficult-to-drug targets. A strong technical interest of the Enchev lab, at the Crick, complimentary and synergistic to the above biological and drug discovery interests, is to enable new avenues of studying biochemical process through the development and application of methods that allow the direct observation of biochemical processes at atomic spatial- and milliseconds time-resolution by combining microfluidics, cryo-electron microscopy (cryo-EM) and single particle analysis aided by machine learning. We utilize microfluidics devices to mix and incubate biochemical samples on sub-second time scales and then rapidly spray-plunge-freeze the reactants for subsequent three-dimensional structure determination by cryo-EM (time-resolved cryo-EM, trEM). Iterating the procedure at increasing incubation times after sample mixing, combined with machine learning based approaches to mapping the conformational landscape at each time point, allows the visualization of a biochemical binding and/or enzymatic reaction as a time-lapse “movie”.

The Project

DNA helicases are indispensable enzymes for key cellular processes like DNA replication, repair, recombination, and transcription (Brosh et al, 2021).  Molecules that deter the DNA damage response machinery enhance deleterious effects of chemo- and radiotherapy on cancer by impairing the proliferative ability of quickly dividing cells that accumulate replicative lesions. Despite significant strides in researching helicase function, many aspects, especially when it comes to their dynamics, remain poorly understood.

Helicases like POLQ stand out as potential drug targets, especially in the context of cancer therapies. While the idea of targeting helicases has been an active area of research, progress is impeded by knowledge gaps related to fundamental aspects of their function, particularly the mechanistic details of unwinding. Two primary models seem to be the most relevant for human helicases: the inchworm model and the Brownian ratchet model (Burnham et al, 2019). The first suggests that helicases move directionally along the nucleic acid strand in a systematic, stepwise manner, analogous to the movement of an inchworm. In contrast, the Brownian ratchet model posits that helicases utilize random, non-directional Brownian motion for translocation, with a ratcheting mechanism preventing backward movement.

We aim to conclusively address such outstanding questions by capturing transient intermediate states of the POLQ helicase domain using trEM. Further, we endeavour to bridge the gap in ATPase driven unwinding activities thus fostering advancements in bioassays and drug discovery paradigms. This proof-of-concept studies, if successful, would not only greatly advance basic biologic understanding but also highlight the importance of understanding structural dynamics for drug discovery.

The Role

The role of a Senior Laboratory Research Scientist in the Crick is diverse and rewarding.

The purpose of this role is to perform biochemical reconstitutions and structural studies relating to the project. Some of the specific aims include but are not limited to:

• In vitro biochemical reconstitution of relevant POLQ constructs and substrates

• Structural studies of above complexes by conventional cryo-EM and single particle analysis

• Application of trEM workflows to the above and related complexes

Key responsibilities will include but are not limited to:

• Experimental design, execution and interpretation

• Data documentation and regular internal presentations

• Dissemination of scientific results through scientific conferences and publications

The post holder will be expected to creatively lead their own project. 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. You will work with highly experienced colleagues and collaborators in an institute that values discovery without boundaries.

Experience and Competencies

The post holder should embody and demonstrate our core Crick values:

Bold; Open; Collegial

Essential

• PhD in biochemistry (and related fields) or in the final stages of PhD submission

• Theoretical and technical expertise in cryo-electron microscopy and single particle analysis and

• Practical experience with protein expression, purification and in vitro protein biochemistry

• 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

Desirable

• Track record of research experience in molecular mechanism of helicases and/or DNA damage and repair pathways

• Research interest in drug discovery

• Experience in high resolution structure determination and model building

• Experience in structure determination of conformationally dynamic systems

About the Crick and AstraZeneca

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.

• 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

AstraZeneca is a global, science-led, patient-centred biopharmaceutical company focusing on discovering, developing, and commercialising prescription medicines for some of the world’s most serious diseases. But we’re more than a global leading pharmaceutical company. At AstraZeneca, we're dedicated to being a Great Place to Work and empowering employees to push the boundaries of science and fuel their entrepreneurial spirit.

Find out what benefits the Crick has to offer:

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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