Publication highlights

Go inside our research

Explore a selection of research case studies from the past five years.

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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Structure of betaglycan

Revealing at high resolution how molecules work together to boost signalling

Researchers at the Crick and the University of Pittsburgh have used x-ray crystallography and cryo-electron microscopy to determine the structures of betaglycan - a co-receptor involved in cell signalling - in complex with the TGF-β protein and its signalling receptors. They found that both domains in betaglycan are involved in ligand binding, demonstrated how this occurs, and revealed that their arrangement also allows for signalling receptor recruitment. The results provide a structural explanation for how betaglycan functions to capture the ligand and hand it over to the receptors in a sequential manner, to selectively enhance TGF-β signalling.

Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling

Published in Nature Communications

Published

Three-dimensional model of the retroviral intasome and chemical structures of some of the clinical HIV-1 integrase inhibitors studied in the lab

TMEM106B: SARS-CoV-2’s secret entrance to the cell

SARS-CoV-2 is known to enter cells using the ACE2 receptor, but the virus can also infect cells that lack ACE2. The Cherepanov lab, together with Crick and international colleagues, have shown that a second protein, TMEM106B, can act as an alternative entry port for the SARS-CoV-2 virus. The E484D mutation in the virus spike enhances TMEM106B use, and antibodies against TMEM106B can stop viral entry, suggesting their potential as therapeutics. Structural studies looking at how TMEM106B and the virus interact showed that TMEM106B engages the spike precisely at its receptor binding motif. The results may explain how SARS-CoV-2 can spread to tissues outside of the respiratory tract and highlight the ability of the virus to switch to an alternative receptor.

TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Published in Cell

Published

Making an autophagosome grow

Autophagy has an important role in cancer and neurodegeneration, and also in processes such as ageing. The ATG9A and ATG2A proteins are essential core members of the autophagosome, the cellular waste disposal unit required for cleanup and recycling of debris such as damaged organelles or proteins. Work from other labs had demonstrated that ATG9A and ATG2A interact, but not how. Now, by integrating data from peptide arrays, crosslinking, and hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, Crick collaborators led by Sharon Tooze’s lab have proposed a molecular model of the ATG9A-2A complex that allows prediction of how the two proteins work together to facilitate autophagosome growth. Mutational analyses targeting the binding interfaces combined with functional activity assays demonstrated the importance of ATG9A-2A complex formation and activity for the creation of autophagosomes. This work sheds light on a vital biological process, and opens the way for further detailed studies.

ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

Published in Molecular Cell

Published

A supramolecular assembly mediates lentiviral DNA integration

Lentiviral IN proteins are notoriously poorly behaved in vitro, and the HIV 1 intasome has eluded structural biologists for over two decades. Prior research resulted in a collection of partial crystal and NMR structures that did not explain how lentiviral integrase synapses viral DNA ends. This paper described the first structure of the lentiviral intasome, solving the long-standing mystery and reconciling years of HIV-1 integrase structural biology and biochemistry.

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Published in Science

Published

Structural basis for retroviral integration into nucleosomes

Here, we described a cryo-EM structure of a retroviral intasome in a functional complex with a nucleosome. The structure revealed a multivalent interface of the viral integration machinery and chromatin, involving both gyres of nucleosomal DNA and histones. Whilst the histone octamer remains intact, the DNA is lifted from its surface to allow for strand transfer at highly preferred integration sites. These data provided a unique snapshot of an enzyme recognizing and acting upon nucleosomal DNA. The structure was the first to illustrate nucleosome flexibility facilitating a biological process and, as such, had far-reaching implications for chromosome biology.

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Published in Nature

Published

Image depicting the structure of the active site of the integrase enzyme bound with the drug bictegravir.

Structural basis of second-generation HIV integrase inhibitor action and viral resistance

HIV integrase inhibitors represent some of the most impactful antimicrobial inhibitors. The second-generation drugs display improved barriers to the emergence of resistance, which spearheaded their worldwide rollout. Yet not even the most advanced compounds are immune to viral resistance. Our results explained the mechanism of viral resistance associated with the most common drug resistance mutations. Furthermore, we established the key difference between the first and second-generation strand transfer inhibitors, which will inform further development of this drug class.

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Published in Science

Published

COVID-19 spike with biliverdin binding site.

SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity

A team led by the Cherepanov lab has found a molecule that can block the binding of a subset of human antibodies to SARS-CoV-2. This could explain patients who, despite having high levels of antibodies, become ill.

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Published in Science advances

Published

Scalable and robust SARS-CoV-2 testing in an academic center

This paper decribes how we were able to successfully repurpose the Crick to increase the capacity for Sars-CoV-2 testing in unpredented times.

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Published in Nature Biotechnology

Published

COVID testing

Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers

This important paper showed very high levels of infection amongst healthcare workers in a local hospital. It has influenced government policy – asymptomatic healthcare workers are to be screened as per our recommendation (announced October 12th).

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Published in The Lancet

Published

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

An example of our work on COVID-19 and of the flexible and collaborative nature of the Crick, involving several labs within the Crick and our collaborating universities and university hospitals. In this work, we described the discovery of pre-existing binding and neutralising antibodies against SARS-CoV-2 in uninfected and unexposed individuals. These antibodies, likely induced by exposure to seasonal coronaviruses, are present in a small percent of adults but in the majority of children, consistent with the relative sparing of the latter from the severe form of COVID-19

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Published in Science

Published

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Find out how we share our research, or go in-depth with some reports on particular research areas.

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Accessing our research

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.