Insight on Research


Dynamic structure of human DNA repair enzyme, ATM, revealed

Dynamic structures ATM graphic

The DNA in cells is constantly damaged by both internal activities of the cell and by external factors such as ionising radiation. In order to function correctly, this damage must be repaired, or if it cannot be repaired, the cell must be killed to prevent development of diseases such as cancer. The large protein kinase, ataxia-telangiectasia mutated (ATM), is a vital component of the cell’s DNA repair machinery.

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The key to GPCR-G protein selectivity

GPCR-G Protein key graphic

G protein-coupled receptors (GPCRs) form the largest family of membrane-protein receptors and drug targets. With over 800 different family members in humans, GPCRs regulate diverse intracellular signalling cascades in different cell types, tissues and organ systems. Whilst GPCRs sense a plethora of environmental stimuli, the appropriate cellular response is primarily triggered by binding to four major Gα protein families encoded by 16 human genes.

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Integral component of the Wnt enhancesome identified

Refined model of Wnt enhanceosome

The Wnt signalling pathway is an ancient cell communication pathway that has important roles in development and cancer. Wnt signals elicit context-dependent transcriptional responses by stabilising a cytoplasmic effector called beta-catenin. This controls the embryonic development of tissues and organs in all animals, from the most primitive ones all the way to humans.

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First complete 3D genome structure from individual mammalian cells

DNA in the nucleus is arranged into nucleosomes to produce an 11nm fibre which then intricately folds into high order assemblies. This nuclear organisation – the 3D arrangement of the genome within the nucleus – is critically linked to nuclear processes. Previously it has only been possible to analyse genome organisation across populations of cells.

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How astrocytes control circadian time-keeping in our principal body clock

Composite image of astrocytes & neurons of the SCN

The suprachiasmatic nucleus of the hypothalamus (SCN) is our principal “body clock”, controlling our daily (circadian) rhythms of physiology and behaviour that adapt us to the 24-hour cycle of day and night.  It ensures that numerous other local tissue clocks distributed across the body are in tune with each other and with the external light-dark cycle.

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New insights into how peptides became a part of the ancient RNA world

Peptides from the ribosome of T. thermophilus

In all present-day organisms, information encoded in DNA, the genetic material of the cell, is converted via an RNA intermediate into proteins, the molecular machines of the cell. However, evidence suggests that in a distant evolutionary past our single-celled ancestors used only RNA for both genetic information storage and metabolism. A cornerstone of this “RNA world” would have been an RNA able to replicate itself.

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The idiosyncratic ribosomes of mitochondria

The overall structure of the complete yeast mitoribosome

Mitochondria are organelles within eukaryotic cells that likely evolved from an ancient bacterium that was engulfed by a primordial eukaryote. Within mitochondria, mitochondrial ribosomes (mitoribosomes) synthesise a subset of essential proteins encoded by the mitochondrial genome.

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Uncovering the molecular basis of triage during protein synthesis

Diagram of triage during protein synthesis

Every minute, cells make millions of new proteins which must be transported to the correct location, folded, modified and assembled with other proteins in order to function properly. Failure at any of these maturation steps can reduce protein function and lead to the accumulation of aberrant protein intermediates, resulting in disease.

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IL-17, a regulator of the immune system, impacts behaviour

Mutant worms feeding alone

The state of the immune system has effects on brain function, but despite suggestions that immunoregulators can affect people’s mood and behaviour, we are only beginning to understand how these two major body systems interact. The contributions of a neuron to circuit activity and behaviour depend on its responsiveness to upstream inputs, and its ability to drive downstream outputs.

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New insights into the structure and dynamics of the catalytic spliceosome

Cartoon representation of the structure of a yeast spliceosome captured just before mRNA formation. Note how second step factors bind on the side of the complex and stabilize the position of the branch helix, thus making space for the 3’-end of the intron in the active site.

The spliceosome is a molecular machine, which together with RNA polymerases and ribosomes plays a critical role in basic gene expression. Research by Kiyoshi Nagai’s group in the LMB’s Structural Studies Division, has previously revealed the structure of the spliceosome in a fully active, substrate-bound state, immediately after its first catalytic reaction. The group has now expanded upon this work revealing the near-atomic level structure of the spliceosome just before mRNA formation.

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