A5056320459- Microtubule and mitosis dynamics
- Monoclonal and Polyclonal Antibodies Research
- Cytomegalovirus and herpesvirus research
- Ion channel regulation and function
- Advanced Electron Microscopy Techniques and Applications
- Glycosylation and Glycoproteins Research
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Herpesvirus Infections and Treatments
- Epigenetics and DNA Methylation
- Photosynthetic Processes and Mechanisms
- Galectins and Cancer Biology
- Virus-based gene therapy research
- Cancer-related gene regulation
- Cardiac electrophysiology and arrhythmias
- Nicotinic Acetylcholine Receptors Study
- RNA and protein synthesis mechanisms
- Hemoglobin structure and function
- Venomous Animal Envenomation and Studies
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Ion Transport and Channel Regulation
- Viral Infectious Diseases and Gene Expression in Insects
Kaiser Permanente South San Francisco Medical Center
2018-2022
Kazusa DNA Research Institute
2018
Novartis (United States)
2014-2016
Global Vaccines (United States)
2016
University of California, Berkeley
2008-2015
GlaxoSmithKline (United States)
2015
Novartis (Switzerland)
2015
European Institute of Oncology
2005-2008
Ripamonti
2005-2007
IFOM
2005
Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, death program important for elimination intracellular bacteria. Precisely how GsdmD triggers pyroptosis has not been established. Here we show human forms functional pores within membranes. When liberated from corresponding C-terminal p20 in presence liposomes, localized to lipid bilayer, whereas...
Polycomb Repressive Complex 2 (PRC2) is essential for gene silencing, establishing transcriptional repression of specific genes by tri-methylating Lysine 27 histone H3, a process mediated cofactors such as AEBP2. In spite its biological importance, little known about PRC2 architecture and subunit organization. Here, we present the first three-dimensional electron microscopy structure human complex bound to cofactor Using novel internal protein tagging-method, in combination with isotopic...
How activation leads to gating Voltage-gated sodium (Na v ) channels are key players in electrical signaling. Central their function is fast inactivation, and mutants that impede this cause conditions such as epilepsy pain syndromes. The have four voltage-sensing domains (VSDs), with VSD4 playing an important role inactivation. Clairfeuille et al. determined the structures of a chimera which cockroach channel Na PaS replaced from human 1.7, both apo state bound scorpion toxin impedes (see...
Clustering for the kill Cluster of differentiation 20 (CD20) is a membrane protein that defines most B cell populations and target therapeutic antibodies to treat malignancies autoimmune disorders. Rougé et al. present structure CD20 bound antibody rituximab activates complement system cells. forms dimer each monomer binds one antigen-binding fragment (Fab) give 2:2 stoichiometry. The compact packing between Fab arms gives rise circular assemblies with diameter similar hexamers known recruit...
Most protein complexes are inaccessible to high resolution structural analysis. We report the results of a combined approach cross-linking, mass spectrometry, and bioinformatics two human containing large coiled-coil segments, NDEL1 homodimer NDC80 heterotetramer. An important limitation cross-linking approach, so far, was identification cross-linked peptides from fragmentation spectra. Our novel overcomes data analysis bottleneck spectrometry. constructed purpose-built database match...
The Ndc80 complex is a constituent of the outer plate kinetochore and plays critical role in establishing stable kinetochore-microtubule interactions required for chromosome segregation mitosis. evolutionarily conserved contains four subunits Spc24, Spc25, Nuf2, (whose human homologue called Hec1). All are predicted to contain globular domains extensive coiled coil regions. To gain an insight into organization complex, we reconstituted it using recombinant methods. hydrodynamic properties...
Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients the leading viral birth defects after congenital infection. The glycoprotein complexes gH/gL/gO gH/gL/UL128/UL130/UL131A (Pentamer) are key targets human humoral response against HCMV required for entry into fibroblasts endothelial/epithelial cells, respectively. We expressed characterized soluble forms gH/gL, gH/gL/gO, Pentamer. Mass spectrometry mutagenesis analysis revealed that gL-Cys144...
Hefty structures of IgA and IgM complexes Immunoglobulin M (IgM) are antibody isotypes that can form higher-order secretory (sIgM sIgA), which allows them to effectively bind neutralize antigens with low-affinity repetitive epitopes, such as those found on the surface many bacteria viruses. The assembly transport these molecules is also dependent joining chain (J-chain) polymeric immunoglobulin receptor (pIgR) component (SC). architecture complex, multimeric has remained elusive. Li et al....
Human cytomegalovirus (HCMV) poses a significant threat to immunocompromised individuals and neonates infected in utero. Glycoprotein B (gB), the herpesvirus fusion protein, is target for neutralizing antibodies vaccine candidate due its indispensable role infection. Here we show crystal structure of HCMV gB ectodomain bound Fab fragment 1G2, human monoclonal antibody isolated from seropositive subject. The gB/1G2 interaction dominated by aromatic residues 1G2 heavy chain CDR3 protruding...
Despite the development of effective therapies, a substantial proportion asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, rodents, TRPA1 is involved induction airway inflammation hyperreactivity. Here, discovery early clinical GDC-0334, highly potent, selective, orally bioavailable antagonist, described. GDC-0334 inhibited function on smooth...
Engineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority molecules that facilitate targeted do so via select number ubiquitin ligases, restricting this therapeutic approach tissue types express requisite ligase. Here, we describe new protein through direct substrate 26S proteasome. proteolytic complex is essential and abundantly expressed all cells; however, proteasomal ligands remain...
Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel inhibitors that could minimize risk drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric identify series 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinesulfonylureas. A leading compound from this advanced into safety studies cynomolgus monkeys, renal toxicity, due precipitation, observed. To overcome obstacle,...
Human Cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients fetuses following congenital infection. The glycoprotein complexes gH/gL/gO gH/gL/UL128/UL130/UL131A (Pentamer) are required for HCMV entry fibroblasts endothelial/epithelial cells, respectively, targeted by potently neutralizing antibodies the infected host. Using purified soluble forms Pentamer as well panel naturally elicited human monoclonal antibodies, we determined location key epitopes on...