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Cell death contributes to tissue homeostasis and plays critical roles in inflammation and host defense. Our increasing understanding of the physiological importance of cell death underlines the need to more fully elucidate its underlying mechanisms in health and disease. Molecular and structural insight into the cell death apparatus could provide strategies to target the loss of cells in pathophysiological contexts. We asked experts studying a range of cell death types to share with us what they are most excited to tackle and what the field needs for progress.

The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).

The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound to BCL-2 and the G101V mutant, revealing the structural basis for venetoclax resistance.

The pseudokinase MLKL is activated by the upstream kinase RIPK3 in the necroptotic pathway but the structural basis of MLKL activation is not well understood yet. Here, the authors present the crystal structures of the human RIPK3:MLKL complex and human RIPK3 kinase alone, which reveal structural differences between human and murine RIPK3 and they discuss mechanistic implications.

How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

Crystal structures of BAK core domain dimers suggest a mechanism by which lipids contribute to the oligomerization of BAK, which is essential for BAK-mediated permeabilization of the mitochondrial outer membrane.

A high-throughput chemical screen followed by structure-guided chemical design leads to the first potent and selective small-molecule BCL-X_L inhibitor.

The pro-survival BCL-2 family of proteins provides exciting drug targets for the selective induction of apoptosis in cancer cells, in which these proteins are often overexpressed. Lessene and colleagues review the preclinical and clinical data for BCL-2 antagonists, and recommend criteria for establishing the mode of action for this new drug class.

The Kir potassium channels are known to operate and gate without a major conformational change. Here, the authors identify the permeation gate of Kir channels as a steric plug within the conduction pathway, describing how tightly associated anionic lipids pushing into fenestrations in the pore walls engage with the plug to operate the gate.

Plasmepsin V is an aspartyl protease essential for export of effector proteins to Plasmodium-infected erythrocytes. A new inhibitor blocks plasmepsin V and inhibits parasite growth; it has also allowed solving the structure of P. vivax plasmepsin V.

A phenotypic screen led to the identification of potent inhibitors of mouse BAK-driven apoptosis. The compounds interact with VDAC2 and stabilize its interaction with BAK, blocking apoptosis at an early stage to preserve long-term cell survival.

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

An engineered Pichia pastoris strain enables the synthesis of tryptophan C-mannosylated proteins, and selected monoclonal antibodies provide tools for detecting these modified proteins and studying their functions.

BCL-2 proteins fulfil important functions in cell death as initiators, guardians and executioners of mitochondrial outer membrane permeabilization. Recent findings demonstrating complex interactions among BCL-2 proteins set forth a comprehensive model of BCL-2 action.

Interactions on the mitochondrial outer membrane between members of the three subgroups of the BCL-2 protein family set the apoptotic threshold. Recent structural insights into the molecular mechanisms of this commitment to apoptosis are guiding the development of new therapeutics for cancer, and potentially also autoimmune and infectious diseases.

Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X_L, which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X_L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer.

RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.

A subnanometre-resolution cryo-electron microscopy structure of the Rh5–CyRPA–Ripr complex of Plasmodium falciparum provides insights into how this ligand interacts with the receptor basigin in erythrocyte hosts.

BH3-mimetic drugs have been designed to directly induce apoptosis in cancer cells by targeting prosurvival BCL-2 family proteins. This Review discusses their continued development and the challenges arising from their implementation in the clinic, such as resistance or on-target toxic effects, and the approaches that could be harnessed to overcome these obstacles.