Structure and dynamics of enterovirus IRES-ribosome complexes

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Enteroviruses (e.g. Poliovirus, Rhinovirus, Coxsackievirus) comprise a diverse group of human and animal pathogens, which together are estimated to cause over one billion infections annually. Once inside the host cell, their positive-sense, single-stranded RNA genomes are directly translated to produce the viral polyprotein. A key event in the infection cycle is the recruitment of host ribosomes to initiate translation. This occurs via an internal ribosome entry site (IRES) in the 5' untranslated region of the genome. The enterovirus type 1 IRES is ~450 nt in length and organized into five structured domains, which interact with trans-acting protein factors (ITAFs) leading to recruitment of 43S complexes. However, our understanding of this network of interactions has been hampered by the lack of any high-resolution three-dimensional structures. Furthermore, a new gene has recently been discovered in some enteroviruses, located upstream of the main polyprotein (Lulla et al., Nat Microbiol, 2019). This exploits an alternate AUG codon located within domain VI of the IRES itself, but the mechanistic basis for start-site selection is not understood. You will study the structural and mechanistic basis of enterovirus initiation at a variety of model IRESs. This will involve the reconstitution of initiation in vitro, purification of initiation complexes, sample optimization, cryo-EM data collection and processing. You will also study protein RNA-interactions between ITAFs and IRES domains using a variety of biophysical and biochemical tools. You will explore key findings in virus-infected cells, in collaboration with the Lulla lab (University of Cambridge). You will join a vibrant, diverse and highly supportive training environment with the combined expertise of three supervisors - ribosome structural biology and protein-RNA interactions (Hill and Plevin labs) and Enterovirus molecular biology (Lulla lab). You will also benefit from access to state-of the art cryo-EM infrastructure at YSBL, and the molecular interactions laboratory at the Biology Technology Facility. Candidates from under-represented groups are particularly encouraged to apply.