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The structure of the IZUMO1–JUNO complex, crucial for sperm–oocyte interaction during fertilization, is reported, providing a first step towards understanding the mechanics of the interaction.

The hepatitis B virus surface protein recognizes host entry receptor via its intrinsically disordered peptide. The authors reveal the dynamic process of the viral surface protein that involves a stepwise binding maturation for establishing high affinity and specific virus-receptor entry complex.

PLD3 and PLD4 are endolysosomal exonucleases that modulate TLR7 and TLR9 responses. The authors report cryoEM structures capturing distinct catalytic states, providing mechanistic insights into single-stranded DNA degradation by PLD3 and PLD4.

LGR4, RSPO and ZNRF3 are key regulators of the Wnt/β-catenin signaling pathway. Here, the authors reveal cryo-EM structures of human LGR4, the LGR4-RSPO2 and LGR4-RSPO2-ZNRF3 complexes, thereby providing structural insights for their regulatory mechanism of Wnt/β-catenin signaling.

NOD2 has a role in host innate immune responses, activating the NF-κB signalling pathway and mutations have been associated with chronic inflammatory disorders. Here, Maekawa et al. solved the structure of NOD2 in its inactive form, suggesting a mechanism for autoinhibition.

Toll-like receptors (TLRs) have key roles in innate immunity. Here, Shimizu and colleagues report crystal structures of TLR8 in complex with single-stranded RNA that reveal the molecular basis for recognition of a natural ligand.

High-throughput screening and hit optimization have led to the development of a small molecule, CIM-834, that targets the SARS-CoV-2 membrane protein and blocks assembly of the virus.

In this study, Asami et al. present the cryo-EM structure of the complex between hepatitis B virus protein and its host entry receptor NTCP, which provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.

Structural and mutational studies and cellular assays show that the inflammasome sensor NLRP1 forms a complex with thioredoxin, which acts as a negative regulator of inflammasome activity.

Cryo-electron microscopy structures of the bile acid transporter NTCP in the apo state and in complex with the preS1 domain of hepatitis B virus (HBV) provide insight into NTCP substrate transport and HBV recognition mechanisms.

M protein plays essential roles in virus assembly and morphogenesis. Here, authors reveal two cryo-EM structures of M protein from SARS-CoV-2 that suggest conformational dynamics of M protein and its role in virus assembly.

TLR3 activates a potent immune response by binding to dsRNA. Here the authors report cryo-EM analyses to show that TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.

Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

Cryo-EM structures of nucleic acid–sensing Toll-like receptors in complex with their trafficking chaperone UNC93B1, a protein that mediates TLR compartmentalization important for self versus non-self discrimination, provide insights into their interaction.

A series of Toll-like receptor 7 (TLR7)-specific antagonists and extensive structural analysis reveal the open conformation of the receptor and the structural basis of TLR7 antagonism. One of the compounds shows efficacy in treating mouse model of systemic lupus erythematosus.

TLR7 triggers immune responses upon sensing microbial RNA, and its endosomal localization is thought to prevent TLR7 activation by host RNA. Here, Kanno et al. show that TLR7 is also present on the surface of immune cells, and that anti-TLR7 antibody can prevent TLR7-mediated autoimmunity.

Discrimination between self and microbial DNA by innate receptors such as TLR9 relies on intracellular compartmentalization to increase specificity. Chan et al. show that activation of TLR9 by DNA ligands requires their processing by endolysosomal DNase II, restricting TLR9 activation to this organelle.

HTL and D14 receptors perceive the structurally similar signaling compounds karrikin and strigolactone. Here, the authors show that ShD14 and a divergent clade of ShHTLs from Strigae capable of recognizing strigolact are capable of recognizing strigolactone and provide structural insights into the evolution of ligand specificity.

High-throughput screening identified potent small-molecule inhibitors of the endosomal Toll-like receptor TLR8 that stabilize the preformed TLR8 dimer in its resting state by binding to a unique site on the inactive dimer interface.

Crystal structures of three forms of Toll-like receptor (TLR) 9 — unliganded or bound either to immune stimulatory CpG-containing DNA or inhibitory DNA — together reveal the molecular basis of TLR9 activation.

Structural and biochemical analysis of double-stranded RNA transporter SIDT1 reveals the conformational change associated with cholesterol binding and the causal relationship between pH, RNA binding, and ceramidase activity.