We wish to appoint a talented and ambitious Research Associate to develop novel approaches to targeting malaria and tuberculosis. Drug resistance is becoming increasingly problematic in malaria and TB, two of the most-deadly diseases in human history. The WHO estimates that there were over half a million cases of drug-resistant TB in 2017. This exciting pilot project is funded by the Bill&Melinda Gates Foundation for 13 months to investigate the feasibility of developing inhibitors of DNA replication in these globally important pathogens.
You will have a Ph.D. (or be close to completion) in a relevant life-sciences subject and experience in X-ray crystallography, structure refinement, protein purification and executing crystallization trials. The successful applicant will conduct world-class research in structure-based drug design to develop inhibitors of microbial flap endonucleases (FENs). FEN enzymes are involved in cellular DNA synthesis and genome damage repair. We have shown that a member of this important class of enzymes contains a novel DNA-binding motif, the helical arch (Al Malki et al, Direct observation of DNA threading in flap endonuclease complexes. 2016, Nature Structural and Molecular Biology, 23, 640-646).
You will facilitate production, crystallization and X-ray crystal structure determination of FEN enzymes and their complexes with inhibitors. You will work closely with a second postdoctoral Research Associate carrying out enzyme production and inhibitor assays as well as with chemo- informatics experts. We welcome highly dedicated and enthusiastic candidates with the ability to develop their scientific skills in the direction of rational drug design.
You will join a multi-disciplinary team spanning two research groups: The Sayers lab is based within the Dept. of Infection, Immunity and Cardiovascular Disease; and the Baker group is housed within the Dept. of Molecular Biology and Biotechnology. This vibrant team works on FEN mechanism and applications in biotechnology as well as inhibitor discovery in other target organisms. We use site- directed mutagenesis, crystallography and kinetic approaches to determine how these complicated enzymes function in order to design inhibitors in conjunction with virtual and physical screening. The groups are housed within well-equipped laboratories with access to excellent core facilities with state-of-the-art equipment for e.g. biological mass spectrometry, nucleic acid sequencing, X-ray crystallography, liquid handling for high throughput screening, crystallization robotics, plus a range of microscopy facilities, etc. The Sayers group hosts a Marie Curie Individual Fellow and PhD students working on homologous FENs derived from bacteria and viruses. For more details of our FEN research see: www.sayers.staff.shef.ac.uk/fen/index.html
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