Publication highlights

Complicated proteins with multiple domains could easily misfold, but the ribosome, where proteins are made, somehow folds them properly. Two teams at the Crick used advanced imaging and chemical techniques to see how the ribosome manages this feat in human cells. They found that protein subdomains fold progressively as they are made, with flexible ends preventing the growing complex from locking in to its final conformation until the complete protein has been made. This controlled timing helps avoid misfolding. Unlike bacteria, where domains connect early and stay fixed, human ribosomes delay these connections, probably to ensure complex, multidomain proteins form correctly.

SAMHD1 is a multi-subunit enzyme that regulates the levels of DNA building blocks in the cell, restricts HIV-1 infection of macrophage and resting T-cells, and has roles in cancer and autoimmune disease. Researchers at the Crick conducted time-resolved cryo-EM imaging to directly visualise this enzyme in action. The study captured SAMHD1 over the assembly, steady-state, and substrate-depleted phases of its catalytic process. The imaging shows how dynamic regulatory domains control substrate access and product release from a stable catalytic core. This direct visualisation provides an unprecedented understanding of the dynamics and regulation of a multi-subunit enzyme.

D-cycloserine is an antibiotic used for decades to treat drug resistant tuberculosis. Its inhibition mechanism came into question when in a previous paper we determined alanine racemase activity in “fully inhibited” cells. This study demonstrated a previously unknown path during the assumed irreversible inhibition of alanine racemase that leads to the destruction of the antibiotic, meaning that alanine racemase is not irreversibly inhibited by the drug. The paper highlights the complexity of studying the chemical mechanisms of inhibition of enzymes and points to a novel strategy to design D-cycloserine analogues with improved properties.

Here we determined the structure by single particle cryo-EM of capsid assembly in an endogenous retrovirus. This is the first atomic resolution structure of a closed capsid shell, which in retroviruses packages and protects the genome. By studying 4 different types of symmetric assemblies, we discovered how the underlying Fullerene geometry is achieved by the CA protein forming both pentamers and hexamers and found structural rules by which invariant pentamers and structurally plastic hexamers associate to form the unique polyhedral structures.

A study led by the West lab has found that blocking a specific protein could increase tumour sensitivity to treatment with PARP inhibitors. Their work suggests that combining treatments could lead to improved therapy for cancer patients.