A5050814492- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Mass Spectrometry Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
- Viral Infections and Vectors
- Marine Sponges and Natural Products
- Animal Virus Infections Studies
- Receptor Mechanisms and Signaling
- Biotin and Related Studies
- Zoonotic diseases and public health
- Bioinformatics and Genomic Networks
- Microbial Metabolic Engineering and Bioproduction
- Computational Drug Discovery Methods
- SARS-CoV-2 detection and testing
- Biosensors and Analytical Detection
- Viral Infections and Outbreaks Research
- Viral gastroenteritis research and epidemiology
- Analytical Chemistry and Chromatography
- Advanced biosensing and bioanalysis techniques
- Virus-based gene therapy research
- Salmonella and Campylobacter epidemiology
- Nanocluster Synthesis and Applications
- Electronic Health Records Systems
- Enzyme function and inhibition
Columbia University Irving Medical Center
2023-2024
Port Macquarie Base Hospital
2024
University of California, San Francisco
2018-2023
Columbia University
2021-2023
La Jolla Bioengineering Institute
2020
University of California, Berkeley
2017
University of California, Davis
2000
Significance During the ongoing COVID-19 pandemic, protein engineering offers a rapid and powerful approach for building therapeutics to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We use computational design, affinity maturation, fusion dimerization domains engineer “receptor traps” based on wild-type angiotensin-converting enzyme II (ACE2), target viral spike-mediated SARS-CoV-2 entry into cells. The optimized ACE2 receptor traps neutralize authentic...
Sense and respond Many signaling pathways start with cellular proteins sensing responding to small molecules. Despite advances in protein design, creating a protein-based sense-and-respond system remains challenging. Glasgow et al. designed binding sites at the interface of heterodimers (see Perspective by Chica). By fusing each monomer one half split reporter, they linked ligand-driven dimerization reporter output. The computational design strategy provides generalizable approach create...
Biological regulation ubiquitously depends on protein allostery, but the regulatory mechanisms are incompletely understood, especially in proteins that undergo ligand-induced allostery with few structural changes. Here we used hydrogen-deuterium exchange mass spectrometry (HDX/MS) to map allosteric effects a paradigm ligand-responsive transcription factor, lac repressor (LacI), different functional states (apo, or bound inducer, anti-inducer, and/or DNA). Although X-ray crystal structures of...
Many protein sequences occupy similar three-dimensional structures known as folds. In nature, folds are well-conserved over the course of evolution, such that there 100,000 times many extant than Despite their common shapes, can adopt wide-ranging functions, raising question: so strongly conserved for purpose maintaining function-driving energetic changes in families? Here we show a set key relationships family bacterial transcription factors (TFs) is using high-resolution hydrogen...
An essential mechanism for SARS-CoV-1 and -2 infection begins with the viral spike protein binding to human receptor angiotensin-converting enzyme II (ACE2). Here we describe a stepwise engineering approach generate set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 cells. These optimized traps tightly bind domain (RBD) prevent entry into host We first computationally designed ACE2-RBD interface using two-stage flexible backbone design process...
Abstract Background Known risk alleles for epithelial ovarian cancer (EOC) account approximately 40% of the heritability EOC. Copy number variants (CNVs) have not been investigated as EOC in a large population cohort. Methods Single nucleotide polymorphism array data from 13 071 cases and 17 306 controls White European ancestry were used to identify CNVs associated with using rare admixture maximum likelihood test gene burden by-probe ratio test. We performed enrichment analysis at known...
The bacterial type III secretion system (T3SS) is an important target for enabling high-titer production of proteins biotechnological interest as well synthetic biology applications that rely on protein delivery to host cells. T3SS forms a membrane-embedded needle complex capped by the translocon and extends into extracellular space. tip in Salmonella enterica consists three proteins: SipB, SipC, SipD. It known knocking out sipD disrupts regulation cause constitutive native proteins....
SUMMARY Current serology tests for SARS-CoV-2 antibodies mainly take the form of enzyme-linked immunosorbent assays or lateral flow assays, with former being laborious and latter expensive often lacking sufficient sensitivity scalability. Here we present development validation a rapid, low-cost solution-based assay to detect in serum, plasma, whole blood, saliva, using rationally designed split luciferase antibody biosensors (spLUC). This new assay, which generates quantitative results as...
Abstract Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutic design aid in studying molecular evolution. Here we present Mapping Areas of Genetic Parsimony In Epitopes (MAGPIE), a publicly available software package for simultaneously visualizing analyzing thousands between single protein or small molecule ligand (the “target”) all its (“binders”). MAGPIE generates an interactive three‐dimensional...
ABSTRACT Sensing and responding to signals is a fundamental ability of living systems, but despite remarkable progress in computational design new protein structures, there no general approach for engineering arbitrary sensors. Here we describe generalizable strategy designing sensor/actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces coupling ligand sensing modular actuation via split reporters. Using this approach, designed sensors that respond...
While bioinformatics reveals patterns in protein sequences and structural biology methods elucidate atomic details of structures, it is difficult to attain equally high-resolution energetic information about conformational ensembles. We present PIGEON-FEATHER, a method for calculating free energies opening (∆Gop) at single- or near-single-amino acid resolution ensembles all sizes from hydrogen exchange/mass spectrometry (HX/MS) data. PIGEON-FEATHER disambiguates reconstructs experimentally...
Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutics design aid in the study of molecular evolution. Here we present MAGPIE (Mapping Areas Genetic Parsimony In Epitopes), a publicly available software package for simultaneously visualizing analyzing thousands between single protein or small molecule ligand (the "target") all its ("binders"). generates an interactive 3D visualization from set complex...
Abstract Allostery, broadly defined as a protein’s functional response to distal perturbations, is fundamental biological regulation. In classical models, allosteric ligand binding produces set of structural changes in the protein, resulting different low-energy conformation. Proteins that undergo ligand-induced allostery with few observable therefore frustrate interpretations by models. Here we used hydrogen-deuterium exchange mass spectrometry (HDX/MS) map effects paradigm...
An important pathogenicity factor of SARS-CoV-2 and related coronaviruses is Nsp1, which suppresses host gene expression stunts antiviral signaling. Nsp1 binds the ribosome to inhibit translation through mRNA displacement induces degradation mRNAs an unknown mechanism. Here we show that Nsp1-dependent shutoff conserved in diverse coronaviruses, but only from β-CoV inhibits binding. The C-terminal domain all Nsp1s confers high-affinity ribosome-binding despite low sequence conservation....