A5071333092- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Enzyme Structure and Function
- Protein Structure and Dynamics
- CAR-T cell therapy research
- RNA and protein synthesis mechanisms
- SARS-CoV-2 and COVID-19 Research
- Chronic Lymphocytic Leukemia Research
- Cell Adhesion Molecules Research
- COVID-19 Clinical Research Studies
- Bacterial Genetics and Biotechnology
- Advanced Biosensing Techniques and Applications
- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- Chemical Synthesis and Analysis
- Bacteriophages and microbial interactions
- Drug Transport and Resistance Mechanisms
- Cancer-related gene regulation
- Alzheimer's disease research and treatments
- Click Chemistry and Applications
- Antibiotic Resistance in Bacteria
- Galectins and Cancer Biology
- Immunodeficiency and Autoimmune Disorders
- HER2/EGFR in Cancer Research
New York University
2017-2025
University School
2020-2024
Philipps University of Marburg
2024
NYU Langone Health
2016-2024
University of Chicago
2010-2023
NYU Langone’s Laura and Isaac Perlmutter Cancer Center
2021-2023
Duke University
2013
University of Oregon
2006
University of Rochester
2002-2003
University of Rochester Medical Center
1998-2002
The fibronectin type III domain (FN3) is a small autonomous folding unit which occurs in many animal proteins involving ligand binding. β-sandwich structure of FN3 closely resembles that immunoglobulin domains. We have prepared phage display library residues two surface loops were randomized. selected mutant FN3s bind to test ligand, ubiquitin, with significant affinities, while the wild-type shows no measurable affinity. A dominant clone was expressed as soluble protein and its properties...
KRAS is the most frequently mutated human oncogene, and inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation inhibitor engagement, we found an SHP2 (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling adaptive resistance G12C-Is in vitro, xenografts, syngeneic KRASG12C-mutant pancreatic ductal...
Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were poor outcome of a prospective, observational cohort 589 critically ill adults, all whom required mechanical ventilation. For subset 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the tract microbiome using metagenomics and...
High degrees of sequence and conformation complexity found in natural protein interaction interfaces are generally considered essential for achieving tight specific interactions. However, it has been demonstrated that antibodies can be built by using an interface with a binary code consisting only Tyr Ser. This surprising result might attributed to yet undefined properties the antibody scaffold uniquely enhance its capacity target binding. In this work we tested generality binary-code...
Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of in addition to site are strongly desirable. Here, we show that an intramolecular interaction between SH2 domains both necessary sufficient for high catalytic activity enzyme. Disruption this interface led inhibition downstream...
Insulin degrading enzyme (IDE) plays key roles in peptides vital type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes that tend to form amyloid fibrils remained unsolved. We used cryoEM understand both apo- insulin-bound dimeric states, revealing displays a large opening between homologous ~55 kDa N- C-terminal halves allow selective substrate capture based on size charge complementarity. also cryoEM, X-ray crystallography,...
Multidrug transporters belonging to the multidrug and toxic compound extrusion (MATE) family expel dissimilar lipophilic cationic drugs across cell membranes by dissipating a preexisting Na + or H gradient. Despite its clinical relevance, transport mechanism of MATE proteins remains poorly understood, largely owing lack structural information on substrate-bound transporter. Here we report crystal structures -coupled transporter NorM from Neisseria gonorrheae in complexes with three distinct...
Building a gate to the nucleus Nuclear pore complexes form gateway between cytoplasm and (see Perspective by Ullman Powers). Stuwe et al. combined structural, biochemical, functional analyses elucidate architecture of six-protein complex that makes up inner ring fungal nuclear pore. This includes central trimeric homologous Nup62 found in metazoans is incorporated into inner-ring complex. Chug report structure metazoan Neither study supports model which can dilate constrict. Instead they...
Phosphorylation of the MLKL pseudokinase by RIPK3 kinase leads to oligomerization, translocation to, and permeabilization of, plasma membrane induce necroptotic cell death. The precise choreography activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind domain within human cells their crystal structures in complex with domain. While Monobody-32 constitutively binds hinge region, Monobody-27 via an epitope overlaps site is only exposed...
The necroptosis cell death pathway has been implicated in host defense and the pathology of inflammatory diseases. While phosphorylation necroptotic effector pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) by upstream protein kinase RIPK3 is a hallmark activation, precise checkpoints signaling are still unclear. Here we have developed monobodies, synthetic binding proteins, that bind N-terminal four-helix bundle (4HB) “killer” domain neighboring first brace helix human MLKL with...
Activating mutants of RAS are commonly found in human cancers, but to date selective targeting the clinic has been limited KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes active state both KRAS(G12V) and up 400-times more tightly than wild-type KRAS. The crystal structures reveal 12VC1 mutations shallow pocket, competes against RAS-effector interaction. When expressed intracellularly, potently inhibits ERK activation proliferation RAS-driven...
Intracellular oncoproteins can be inhibited with targeted therapy, but responses are not durable. Immune therapies curative, most oncogene-driven tumors unresponsive to these agents. Fragments of intracellular act as neoantigens presented by the major histocompatibility complex (MHC), recognizing minimal differences between and their normal counterparts is challenging. We have established a platform technology that exploits hapten-peptide conjugates generated covalent inhibitors create...
A challenge in understanding the mechanism of protein function biology is to establish correlation between functional form intracellular environment and high-resolution structures obtained with vitro techniques. Here we present a strategy probe conformational changes proteins inside cells. Our method involves: (i) engineering binding different conformations target protein, (ii) using them sense surface property We probed ligand-induced estrogen receptor alpha (ER alpha) ligand-binding domain...
Antibodies that bind protein antigens are indispensable in biochemical research and modern medicine. However, knowledge of RNA-binding antibodies their application the ever-growing RNA field is lacking. Here we have developed a robust approach using synthetic phage-display library to select specific antigen-binding fragments (Fabs) targeting large functional RNA. We solved crystal structure first Fab-RNA complex at 1.95 A. Capability phasing contact formation suggests Fab provides...