A5009470526- RNA and protein synthesis mechanisms
- Domain Adaptation and Few-Shot Learning
- Microbial Metabolic Engineering and Bioproduction
- Multimodal Machine Learning Applications
- Human Pose and Action Recognition
- Animal Virus Infections Studies
- Microbial Natural Products and Biosynthesis
- Viral gastroenteritis research and epidemiology
- Bacteriophages and microbial interactions
- Microtubule and mitosis dynamics
- Video Analysis and Summarization
- Viral Infections and Immunology Research
- Enzyme Structure and Function
- Generative Adversarial Networks and Image Synthesis
- Virology and Viral Diseases
- RNA modifications and cancer
- Protein Structure and Dynamics
- Virus-based gene therapy research
- Rabies epidemiology and control
- Bacterial Genetics and Biotechnology
- Viral Infections and Outbreaks Research
- Advanced Image and Video Retrieval Techniques
- Photosynthetic Processes and Mechanisms
- Plant biochemistry and biosynthesis
- Viral Infections and Vectors
Harvard University
2015-2024
Adobe Systems (United States)
2021-2024
Triemli Hospital
2022
Boston University
2020
ETH Zurich
2006-2009
École Polytechnique Fédérale de Lausanne
2003-2004
The homodimeric mammalian fatty acid synthase is one of the most complex cellular multienzymes, in that each 270-kilodalton polypeptide chain carries all seven functional domains required for synthesis. We have calculated a 4.5 angstrom-resolution x-ray crystallographic map porcine synthase, highly homologous to human multienzyme, and placed template structures individual catalytic responsible cyclic elongation chains into electron density. positioning reveals architecture multienzyme...
We report crystal structures of the 2.6-megadalton alpha6beta6 heterododecameric fatty acid synthase from Thermomyces lanuginosus at 3.1 angstrom resolution. The alpha and beta polypeptide chains form six catalytic domains required for synthesis numerous expansion segments responsible extensive intersubunit connections. Detailed views all active sites provide insights into substrate specificities mechanisms reveal their unique characteristics, which are due to integration multienzyme. mode...
In the multifunctional fungal fatty acid synthase (FAS), acyl carrier protein (ACP) domain shuttles reaction intermediates covalently attached to its prosthetic phosphopantetheine group between different enzymatic centers of cycle. Here, we report structure Saccharomyces cerevisiae FAS determined at 3.1 angstrom resolution with ACP stalled active site ketoacyl synthase. The contacts base chamber through conserved, charge-complementary surfaces, which optimally position toward catalytic cleft...
ClpXP is an ATP-dependent protease in which the ClpX AAA+ motor binds, unfolds, and translocates specific protein substrates into degradation chamber of ClpP. We present cryo-EM studies E. coli enzyme that show how asymmetric hexameric rings bind symmetric heptameric ClpP interact with substrates. Subunits hexamer assume a spiral conformation two-residue segments substrate axial channel, as observed for other proteases protein-remodeling machines. Strictly sequential models ATP hydrolysis...
Significance Enveloped viruses—those with a lipid-bilayer membrane such as influenza, dengue, and human immunodeficiency viruses—enter cells by fusion of the viral cell. A surface glycoprotein, known its “fusion protein,” facilitates this step. Previous work studying kinetics single virus particles fusing target has outlined mechanism which conformational changes in protein accelerate merger two bilayers. In paper, we extend that to structurally distinct class proteins, providing strong...
Nonsegmented negative-stranded (NNS) RNA viruses, among them the virus that causes rabies (RABV), include many deadly human pathogens. The large polymerase (L) proteins of NNS viruses carry all enzymatic functions required for viral messenger (mRNA) transcription and replication: polymerization, mRNA capping, cap methylation. We describe here a complete structure RABV L bound with its phosphoprotein cofactor (P), determined by electron cryo-microscopy at 3.3 Å resolution. complex closely...
The large (L) proteins of non-segmented, negative-strand RNA viruses are multifunctional enzymes that produce capped, methylated, and polyadenylated mRNA replicate the viral genome. A phosphoprotein (P), required for efficient RNA-dependent polymerization from ribonucleoprotein (RNP) template, regulates function conformation L protein. We report structure vesicular stomatitis virus in complex with its P cofactor determined by electron cryomicroscopy at 3.0 Å resolution, enabling us to...
The conserved Ndc80 kinetochore complex, Ndc80c, is the principal link between mitotic spindle microtubules and centromere-associated proteins. We used AlphaFold 2 (AF2) to obtain predictions of ‘loop’ structure : Nuf2 globular head domains that interact with Dam1 subunit heterodecameric DASH/Dam1 complex (Dam1c). guided design crystallizable constructs, structures close predicted ones. a stiff, α-helical ‘switchback’ structure; AF2 positions preferential cleavage sites indicate flexibility...
All steps of fatty acid synthesis in fungi are catalyzed by the synthase, which forms a 2.6-megadalton alpha6beta6 complex. We have determined molecular architecture this multienzyme fitting structures homologous enzymes that catalyze individual reaction pathway into 5 angstrom x-ray crystallographic electron density map. The huge assembly contains two separated chambers, each equipped with three sets active sites distances up to approximately 130 angstroms, across acyl carrier protein...
Significance eIF4E is critical for protein synthesis and becomes hyperactive in cancer cells. Small-molecule inhibitors of the eIF4E/eIF4G initiation factor complex have recently been found to exhibit antitumor activity vitro vivo. However, their mode action at atomic level has remained elusive. Here, we report high-resolution crystal structures complexes 4EGI-1 analogue with eIF4E. We find that inhibition eIF4G binding must be allosteric, because bind distant epitopes on Compound induces...
Kinetochores connect mitotic-spindle microtubules with chromosomes, allowing microtubule depolymerization to pull chromosomes apart during anaphase while resisting detachment as the shortens. The heterodecameric DASH/Dam1 complex (DASH/Dam1c), an essential component of yeast kinetochores, assembles into a microtubule-encircling ring. ring associates rodlike Ndc80 complexes organize kinetochore-microtubule interface. We report cryo-electron microscopy structure (at ~4.5-angstrom resolution)...
Rotaviruses, like other non-enveloped, double-strand RNA viruses, package an RNA-dependent polymerase (RdRp) with each duplex of their segmented genomes. Rotavirus cell entry results in loss outer protein layer and delivery into the cytosol intact, inner capsid particle (the “double-layer particle,” or DLP). The RdRp, designated VP1, is active inside DLP; VP1 achieves many rounds mRNA transcription from its associated genome segment. Previous work has shown that one molecule lies close to...
Vesicular stomatitis virus (VSV) is a negative-strand RNA with non-segmented genome, closely related to rabies virus. Both have characteristic bullet-like shapes. We report the structure of intact, infectious VSV particles determined by cryogenic electron microscopy. By compensating for polymorphism among viral computational classification, we obtained reconstruction shaft ("trunk") at 3.5 Å resolution, lower resolution rounded tip. The ribonucleoprotein (RNP), genomic complexed...
Baculoviruses are insect-infecting pathogens with wide applications as biological pesticides, in vitro protein production vehicles and gene therapy tools. Its cylindrical nucleocapsid, which encapsulates protects the circular double-stranded viral DNA encoding proteins for replication entry, is formed by highly conserved major capsid VP39. The mechanism VP39 assembly remains unknown. We use electron cryomicroscopy to determine a 3.2 Å helical reconstruction of an infectious nucleocapsid...
Self-supervised approaches for video have shown impressive results in understanding tasks. However, unlike early works that leverage temporal self-supervision, current state-of-the-art methods primarily rely on tasks from the image domain (e.g., contrastive learning) do not explicitly promote learning of features. We identify two factors limit existing self-supervision: 1) are too simple, resulting saturated training performance, and 2) we uncover shortcuts based local appearance statistics...
Rotaviruses infect cells by delivering into the cytosol a transcriptionally active inner capsid particle (a "double-layer particle": DLP). Delivery is function of third, outer layer, which drives uptake from cell surface small vesicles DLPs escape. In published work, we followed stages rhesus rotavirus (RRV) entry live-cell imaging and correlated them with structures cryogenic electron microscopy tomography (cryo-EM cryo-ET). The virus appears to wrap itself in membrane, leading complete...