A5002873716- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Cytokine Signaling Pathways and Interactions
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Enzyme function and inhibition
- Chemokine receptors and signaling
- Receptor Mechanisms and Signaling
- CAR-T cell therapy research
- Protein Structure and Dynamics
- Psoriasis: Treatment and Pathogenesis
- Chemical Reactions and Mechanisms
- Immune Response and Inflammation
- Chemical Synthesis and Analysis
- Cancer Immunotherapy and Biomarkers
- PARP inhibition in cancer therapy
- Synthesis and Catalytic Reactions
- Wnt/β-catenin signaling in development and cancer
- Medical Imaging Techniques and Applications
- Radiopharmaceutical Chemistry and Applications
- Protein Tyrosine Phosphatases
- Atomic and Subatomic Physics Research
- Mycobacterium research and diagnosis
Stanford University
2016-2025
Howard Hughes Medical Institute
2015-2024
Stanford Medicine
2022
Cellular Research (United States)
2016
Cancer Institute (WIA)
2016
Stanford Cancer Institute
2016
QB3
2013
University of California, Berkeley
2009
University of Pennsylvania
2002-2008
North Dakota State University
2006-2007
Small-cell lung cancer (SCLC) is a highly aggressive subtype of with limited treatment options. CD47 cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found expressed the surface human SCLC cells; therefore, investigated CD47-blocking immunotherapies potential approach for treatment. Disruption interaction SIRPα using anti-CD47 antibodies induced macrophage-mediated...
Abstract The design of proteins that bind to a specific site on the surface target protein using no information other than three-dimensional structure remains challenge 1–5 . Here we describe general solution this problem starts with broad exploration vast space possible binding modes selected region surface, and then intensifies search in vicinity most promising modes. We demonstrate applicability approach through de novo 12 diverse targets different shapes properties. Biophysical...
Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially engineered cells in adoptive immunotherapy, but its pleiotropy leads to simultaneous stimulation suppression of immune responses as well systemic toxicity, limiting therapeutic use. We IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native signals, do not their natural receptor counterparts. Introduction orthoIL-2Rβ into enabled the...
Molecular “go” signals reveal their secrets Chemokines are proteins that direct how cells move within the body. For instance, chemokines help immune locate invading pathogens and ensure position themselves correctly a developing organ. Cells detect through G protein–coupled receptors on surface; however, molecular details of these interact remain unclear (see Perspective by Standfuss). Qin et al. solved crystal structure chemokine receptor CXCR4 bound to viral vMIP-II. Burg domain CX3CL1....
An interaction that guides cell fate Notch signaling is important in determination mammals. Signaling initiated when the extracellular domain of transmembrane protein on one binds to a surface ligand another cell. Luca et al. report crystal structure interacting regions and Delta-like DLL-4. The modified by O-linked glycan addition, this required for signaling. shows two interfaces. A anchors less conserved interface, which potentially provides flexible way regulating interactions during...
Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure full-length JAK1 complexed with a cytokine domain Box1 and Box2 regions captured as an activated homodimer bearing valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains form extended structural unit, dimerization which is mediated by close-packing pseudokinase (PK)...
Adoptive cell therapy using engineered T receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide-major histocompatibility complexes (pMHCs). Affinity-matured can enhance the efficacy of TCR-T also cross-react with off-target resulting in organ immunopathology. We developed an alternative strategy isolate TCR mutants that exhibited high activation signals coupled low-affinity pMHC binding...
Exploring a range of signaling Cytokines are small proteins that bind to the extracellular domains transmembrane receptors activate pathways inside cell. They often act by dimerizing their receptors, and changes in dimer orientation can change output. Mohan et al. systematically explored this tuning effect designing series ligands for erythropoietin receptor which they varied distance angle between monomers. The topology affected strength activation differentially different pathways, raises...
Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which essential regulators of stem cell biology, yet structural basis signaling through Fzd remains poorly understood. Here we report structure an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with aid antibody chaperone acting as a fiducial marker. We also analyzed topology low-resolution XWnt8/Fzd5 complex particles, revealed extreme flexibility between Wnt/Fzd-CRD and Fzd-TM regions. Analysis...
Abstract The IL-17 family of cytokines and receptors have central roles in host defence against infection development inflammatory diseases 1 . compositions structures functional ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator type 2 immune responses driver diseases, such allergic asthma, requires both receptor A (IL-17RA) IL-17RB to elicit Here we studied IL-25–IL-17RB binary IL-25–IL-17RB–IL-17RA ternary complexes using combination...
Monoclonal antibodies (Abs) that recognize major histocompatability complex (MHC)-presented tumor antigens in a manner similar to T cell receptors (TCRs) have great potential as cancer immunotherapeutics. However, isolation of 'TCR-mimic' (TCRm) Abs is laborious because not evolved the structurally nuanced peptide-MHC restriction αβ-TCRs. Here, we present strategy for rapid highly peptide-specific and 'MHC-restricted' by re-engineering preselected engage conventional We created...
Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate β-catenin signaling. The cryo-EM structure a initiation complex an affinity-matured XWnt8–Frizzled8–LRP6 elucidates basis coreceptor discrimination by canonical means their N termini linker domains that engage LRP6 E1E2 domain funnels. Chimeric bearing modular...
Fine-tuning of protein-protein interactions occurs naturally through coevolution, but this process is difficult to recapitulate in the laboratory. We describe a platform for synthetic coevolution that can isolate matched pairs interacting muteins from complex libraries. This large dataset coevolved complexes drove systems-level analysis molecular recognition between Z domain–affibody spanning wide range structures, affinities, cross-reactivities, and orthogonalities, captured broad spectrum...
Abstract In natural proteins, structured loops have central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility irregularity loop regions, organizing multiple at protein functional sites has been very difficult to achieve by de novo design. Here we describe a solution this problem that designs tandem repeat proteins with (9–14 residues) buttressed extensive hydrogen bonding interactions. Experimental characterization shows...