A5060154356- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- X-ray Diffraction in Crystallography
- Click Chemistry and Applications
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Prostate Cancer Treatment and Research
- Estrogen and related hormone effects
- Protein Structure and Dynamics
- Carbohydrate Chemistry and Synthesis
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Mass Spectrometry Techniques and Applications
- Alzheimer's disease research and treatments
- Biochemical and Structural Characterization
- Metal-Organic Frameworks: Synthesis and Applications
- Advanced Electron Microscopy Techniques and Applications
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Endoplasmic Reticulum Stress and Disease
- Supramolecular Self-Assembly in Materials
- Parkinson's Disease Mechanisms and Treatments
- Supramolecular Chemistry and Complexes
University of Washington
2022-2024
University of Southern California
2017-2024
New York University
2012-2016
New York Proton Center
2013-2014
University of California, Santa Cruz
2007
Significance Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here, we examine consequences O-GlcNAcylation on toxicity α-synuclein, aggregating protein Parkinson’s disease. α-Synuclein modified by O-GlcNAc at least nine different positions vivo, but most these modifications are unknown. use synthetic chemistry to prepare six O-GlcNAcylated forms α-synuclein show that they have largely...
Many peptide hormones form an α-helix on binding their receptors
In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information a manner analogous how transistors control flow computing devices. Designing with distinct but fully structured is challenge for protein design as it requires sculpting an energy landscape minima. Here we describe the of “hinge” populate one designed state absence ligand and second presence ligand. X-ray crystallography, electron microscopy, double...
Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered composed of alpha, beta, gamma, and 17 other acid backbone chemistries, which we used predict 14.9 million closed cycles >42,000 monomer combinations. chemically synthesized 18 predicted adopt single low-energy states determined their x-ray nuclear magnetic...
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety post-translational modifications. One such modification, O-GlcNAcylation, has been found on some these prone proteins, α-synuclein, the major protein that plays causative role in synucleinopathies like Parkinson's disease. We previously used synthetic chemistry to prepare α-synuclein bearing homogeneous O-GlcNAc modification at threonine 72 and showed this inhibits...
We describe an approach for designing high-affinity small molecule–binding proteins poised downstream sensing. use deep learning–generated pseudocycles with repeating structural units surrounding central binding pockets widely varying shapes that depend on the geometry and number of repeat units. dock molecules interest into most shape complementary these pseudocycles, design interaction surfaces high affinity, experimentally screen to identify designs highest affinity. obtain binders four...
Programming protein nanomaterials to respond changes in environmental conditions is a current challenge for design and important targeted delivery of biologics. Here we describe the octahedral non-porous nanoparticles with targeting antibody on two-fold symmetry axis, designed trimer programmed disassemble below tunable pH transition point three-fold tetramer four-fold axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components,...
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...
Abstract Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs their cognate peptides vitro nanomolar affinities. crystal structure protein−peptide complex is close the design model, NMR characterization reveals how cleft protected apo state. use binders...
Synthetic proteins bearing site-specific posttranslational modifications have revolutionized our understanding of their biological functions in vitro and vivo. One such modification, O-GlcNAcylation, is the dynamic addition β-N-acetyl glucosamine to side chains serine threonine residues proteins, yet impact O-GlcNAcylation remains difficult evaluate vivo because potential for enzymatic removal by endogenous O-GlcNAcase (OGA). Thioglycosides are generally perceived be enzymatically stable...
ABSTRACT The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based for peptide design deep-learning protein design, there currently no robust approaches de novo protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline designing against targets interest. We test 20 or fewer...
We introduce a family of multivalent peptidomimetic conjugates that modulate the activity androgen receptor (AR). Bioactive ethisterone ligands were conjugated to set sequence-specific peptoid oligomers. Certain enhance AR-mediated transcriptional activation. identify linear and cyclic conjugate exhibit potent anti-proliferative in LNCaP-abl cells, model therapy-resistant prostate cancer. The blocks AR action by competing for ligand binding. In contrast, is active despite its inability...
Peptide agonists of GPCRs and other receptors are powerful signaling molecules with high potential as biological tools therapeutics, but they typically plagued by instability short half-lives in vivo. Nature uses protein glycosylation to increase the serum stability secreted proteins. However, these extracellular modifications complex heterogeneous structure, making them an impractical solution. In contrast, intracellular proteins subjected a simple version termed O-GlcNAc modification. our...
Chemical ligation protocols were explored for generating semisynthetic peptoid–protein hybrid architectures containing a native serine residue at the site. Peptoid oligomers bearing C-terminal salicylaldehyde esters synthesized and ligated to N-terminus of RNase S protein or therapeutic hormone PTH(1–34) polypeptide. This technique will expand repertoire strategies enable design macromolecules with novel structures functions not accessible fully biosynthesized proteins.
Development of elaborate three-dimensional multivalent displays appended on natural or synthetic molecular scaffolds.
Abstract Many peptide hormones form an alpha-helix upon binding their receptors 1–4 , and sensitive detection methods for them could contribute to better clinical management. De novo protein design can now generate binders with high affinity specificity structured proteins 5,6 . However, the of interactions between short helical peptides is unmet challenge. Here, we describe parametric generation deep learning-based designing address this We show that RF diffusion generative model, picomolar...
Abstract A general method for designing proteins to bind and sense any small molecule of interest would be widely useful. Due the number atoms interact with, binding molecules with high affinity requires highly shape complementary pockets, transducing events into signals is challenging. Here we describe an integrated deep learning energy based approach complementarity binders that are poised downstream sensing applications. We employ generated psuedocycles repeating structural units...
There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of making it attractive target antibacterial drug discovery. Although natural inhibitors LspA have been identified, such as cyclic depsipeptide globomycin, poor stability and production difficulties limit their use clinical setting. We...
The precise recognition of specific peptide-MHC (pMHC) complexes by T-cell receptors (TCRs) plays a key role in infectious disease, cancer and autoimmunity. A critical step many immunobiological studies is the identification T-cells expressing TCRs to given pMHC antigen. However, intrinsic instability empty class-I MHCs limits their soluble expression Escherichia coli (E. coli) makes it very difficult characterize even small fraction possible pMHC/TCR interactions. To overcome this...
Abstract Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends recently developed therapeutics, including enzalutamide. Therefore, new strategies block androgen receptor (AR) function in are required. Here, we report the characterization multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6),...