The resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex.

The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the "open and extended" conformation seen in detergent( ), the unliganded TCR-CD3 in nanodiscs adopts two related "closed and compacted" conformations that represent its physiologic resting state .

Predicting and reasoning about replicability using structured groups.

This paper explores judgements about the replicability of social and behavioural sciences research and what drives those judgements. Using a mixed methods approach, it draws on qualitative and quantitative data elicited from groups using a structured approach called the IDEA protocol ('investigate', 'discuss', 'estimate' and 'aggregate'). Five groups of five people with relevant domain expertise evaluated 25 research claims that were subject to at least one replication study.

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process.

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences.

Structure-Based Discovery of a Novel Class of Small-Molecule Pure Antagonists of Integrin αVβ3.

Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part a charge-charge interaction between their aspartic acid carboxyl group and the metal ion in the metal-ion-dependent adhesion site (MIDAS). Building upon our previous studies on the related integrin αIIbβ3, we searched for pure αVβ3 antagonists that lack this typical aspartic acid carboxyl group and instead engage through direct binding to one of the coordinating residues of the MIDAS metal ion, specifically β3 E220.

Shelterin is a dimeric complex with extensive structural heterogeneity.

Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been generated of the individual structured domains within shelterin, the architecture and stoichiometry of the full complex are currently unknown. Here, we report the purification of shelterin subcomplexes and reconstitution of the entire complex using full-length, recombinant subunits.

Cryo-EM structure of the human CST-Polα/primase complex in a recruitment state.

The CST-Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST-Polα/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking.

Reimagining peer review as an expert elicitation process.

Journal peer review regulates the flow of ideas through an academic discipline and thus has the power to shape what a research community knows, actively investigates, and recommends to policymakers and the wider public. We might assume that editors can identify the 'best' experts and rely on them for peer review. But decades of research on both expert decision-making and peer review suggests they cannot.

An ensemble of flexible conformations underlies mechanotransduction by the cadherin-catenin adhesion complex.

The cadherin-catenin adhesion complex is the central component of the cell-cell adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction complex formed by the α-catenin•β-catenin•epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and β-catenin.

Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β.

Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates.

A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) family, plays diverse roles in mammalian development. It is synthesized as a large, inactive precursor protein containing a prodomain, pro-GDF11, and exists as a homodimer. Activation requires two proteolytic processing steps that release the prodomains and transform latent pro-GDF11 into active mature GDF11.

Cog-Wheel Octameric Structure of RS1, the Discoidin Domain Containing Retinal Protein Associated with X-Linked Retinoschisis.

RS1, also known as retinoschisin, is a disulphide-linked, discoidin domain containing homo-oligomeric protein that plays a crucial role in maintaining the cellular and synaptic organization of the retina. This is highlighted by the finding that over 130 mutations in RS1 cause X-linked retinoschisis, a retinal degenerative disease characterized by the splitting of the retinal cell layers, disruption of the photoreceptor-bipolar synapses, degeneration of photoreceptors, and severe loss in central vision. In this study, we investigated the arrangement of the RS1 subunits within the oligomer complex using single particle electron microscopy.

Structural mechanism of ligand activation in human GABA(B) receptor.

Human GABA(B) (γ-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound and antagonist-bound forms.

Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2.

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABA(B) receptor is a G protein-coupled receptor central to mammalian brain function. Malfunction of GABA(B) receptor has been implicated in several neurological disorders.