Ian Taylor group

Macromolecular assemblies

Many of the fundamental processes carried out within living cells are directed by macromolecular assemblies of protein and nucleic acid molecules, often referred to as “Molecular Machines”. Malfunction of a molecular machine resulting in the breakdown of a normal cellular process is the cause of many human cancers, developmental defects, neurological disorders and other congenital disease states. In order to prevent, combat or repair defects that lead to disease it is vital that we understand how the macromolecular components of molecular machines assemble, function and co-operate with one another in order to carry out complex biological processes.

To understand how molecular machines function and perform their biological task we study molecular assemblies by applying structural, biophysical and biochemical methodologies. These approaches allow us to dissect a macromolecular complex, visualise the components and examine the interactions between the molecules that make up the complex. Current projects include examining complexes that mediate transcriptional elongation, 3’-end processing and polyadenylation (Pancevac et al, 2010; Noble et al, 2007), analysis of the interaction of the retroviral capsid with host factors (Hilditch et al, 2011; Goldstone et al, 2010) and structural studies of host-cell anti retroviral restriction factors (Goldstone et al, 2011; Ohkura et al, 2011).

Figure 1

Figure 1

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The RNA binding domain from the 3’-end processing factor Rna15 bound to either a G (Left) or U (Right) ribonucleotide. The structures reveal an unexpected and conserved GU base selectivity mechanism employed by 3'-end processing complexes to interact with sequence elements at 3'-end of genes1.

Figure 2

Figure 2

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The structure of the RELIK capsid bound to the host cell factor CypA. The RELIK-CypA complex is shown in cartoon representation on the left, RELIK in blue, CypA in green. Details of the RELIK-CypA molecular interface are shown on the right. This structure and combined virological studies of prehistoric lentiviruses revealed the nature of the evolutionary conserved interaction of retroviruses with the host cell protein cyclophilin-A2.

Figure 3

Figure 3

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The structure of the HIV-1 restriction factor SAMHD1 with bound dGTP. The SAMHD1 dimer is shown on the left. Individual monomers coloured in magenta and gold and two bound dGTP molecules are shown in stick representation. The molecular details of the linkage between the allosteric and active sites are shown on the right. The structure and combined biochemical studies provides the basis for SAMHD1 inhibition of HIV-1 infection of dendritic cells and macrophages.

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