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Drug-controlled DROP-CARs enable reversible extracellular control of CAR T cell function via human-derived protein switches that modulate cell–cell interactions and support dual-antigen targeting as well as logic-gated signaling.

A deep-learning-based de novo design strategy was developed that enables simultaneous scaffolding of three distinct epitopes derived from respiratory syncytial virus within small single-domain immunogens. Crystallographic analyses confirmed precise presentation of the designed motifs. The multiepitope constructs elicited enhanced cross-reactive and neutralizing antibody responses, demonstrating the potential of generative models for complex multisite protein engineering.

BindCraft, an open-source, automated pipeline for de novo protein binder design with experimental success rates of 10–100%, leverages AlphaFold2 weights to generate binders with nanomolar affinity without the need for high-throughput screening.

Cathepsins are relevant therapeutic targets in cancer and other diseases. Here, the authors developed a different approach to block the activity of cathepsins in specific cellular contexts by combining non-natural peptide inhibitors with antibodies, enhancing therapeutic efficacy while reducing side effects.

A computational deep learning approach is used to design synthetic proteins that target the neosurfaces formed by protein–ligand interactions, with applications in the development of new therapeutic modalities such as molecular glues or cell-based therapies.

A deep learning approach enables accurate computational design of soluble and functional analogues of membrane proteins, expanding the soluble protein fold space and facilitating new approaches to drug screening and design.

Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions into OFF- and ON-switches active in cells.

Domain insertion into the loop region of AcrIIC1 leads to a variant with enhanced inhibitory activity toward Neisseria meningitides Cas9, while structure-guided design turns AcrIIC1 into a potent inhibitor of Staphylococcus aureus Cas9.

Beginning with a functional site and building a supporting scaffold around it enables the de novo design of proteins with distinct binding motifs for use in biosensors to detect antibody responses and as ligands of synthetic signaling receptors.

A surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling the de novo design of protein interactions and of artificial proteins with function.

Abl is a cytoplasmic tyrosine kinase important for growth, whose hyper activation is associated with several types of cancers. Here, the authors use recombinant Abl protein to uncover the molecular mechanism underlying allosteric activation of Abl by its SH2 domain through the regulation of autophosphorylation.

Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.

The Bcr-Abl tyrosine kinases p210 and p190 are linked to different leukemias and differ by the Dbl homology (DH) and Pleckstrin-homology (PH) domains. Here the authors characterize structures of the Bcr-Abl p210 DH and PH domains and find that the PH domain is important for the cellular localization and signaling network of p210.