A5007320992- Atherosclerosis and Cardiovascular Diseases
- SARS-CoV-2 and COVID-19 Research
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Advanced biosensing and bioanalysis techniques
- Biomarkers in Disease Mechanisms
- Immunotherapy and Immune Responses
- Computational Drug Discovery Methods
- Fibroblast Growth Factor Research
- Enzyme Structure and Function
- RNA Interference and Gene Delivery
- Cardiovascular Disease and Adiposity
- Calpain Protease Function and Regulation
- Immune Response and Inflammation
- Advanced Biosensing Techniques and Applications
- Cellular transport and secretion
- Adipokines, Inflammation, and Metabolic Diseases
- COVID-19 Clinical Research Studies
- CAR-T cell therapy research
- SARS-CoV-2 detection and testing
- Bacteriophages and microbial interactions
- Nanowire Synthesis and Applications
- Epigenetics and DNA Methylation
- Biosensors and Analytical Detection
University of Washington
2019-2025
Westlake University
2021-2024
Weifang Medical University
2024
State Key Laboratory of Oncogene and Related Genes
2024
Renji Hospital
2024
Shanghai Cancer Institute
2024
Center for Excellence in Molecular Cell Science
2016-2024
The University of Texas Southwestern Medical Center
2024
Shanghai Advanced Research Institute
2024
Chinese Academy of Sciences
2016-2024
Targeting the interaction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and human angiotensin-converting enzyme (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with binding domain (RBD) or docked against RBD to identify new modes, their amino acid sequences optimize target binding, folding, stability. Ten...
Abstract The design of proteins that bind to a specific site on the surface target protein using no information other than three-dimensional structure remains challenge 1–5 . Here we describe general solution this problem starts with broad exploration vast space possible binding modes selected region surface, and then intensifies search in vicinity most promising modes. We demonstrate applicability approach through de novo 12 diverse targets different shapes properties. Biophysical...
Abstract De novo enzyme design has sought to introduce active sites and substrate-binding pockets that are predicted catalyse a reaction of interest into geometrically compatible native scaffolds 1,2 , but been limited by lack suitable protein structures the complexity sequence–structure relationships. Here we describe deep-learning-based ‘family-wide hallucination’ approach generates large numbers idealized containing diverse pocket shapes designed sequences encode them. We use these...
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow rapidly screen optimize constructs containing multiple computationally designed miniprotein inhibitors SARS-CoV-2. We found broadest efficacy was achieved with homotrimeric version 75-residue angiotensin-converting enzyme (ACE2) mimic AHB2 (TRI2-2) geometrically match trimeric spike architecture....
As a result of evolutionary selection, the subunits naturally occurring protein assemblies often fit together with substantial shape complementarity to generate architectures optimal for function in manner not achievable by current design approaches. We describe "top-down" reinforcement learning-based approach that solves this problem using Monte Carlo tree search sample conformers context an overall architecture and specified functional constraints. Cryo-electron microscopy structures...
Despite the introduction of public health measures and spike protein-based vaccines to mitigate COVID-19 pandemic, SARS-CoV-2 infections deaths continue have a global impact. Previously, we used structural design approach develop picomolar range miniproteins targeting receptor-binding domain. Here, investigated capacity modified versions one lead miniprotein, LCB1, protect against SARS-CoV-2-mediated lung disease in mice. Systemic administration LCB1-Fc reduced viral burden, diminished...
Abstract Diffusion-based generative models have been successfully employed to create proteins with novel structures and functions. However, the construction of such typically depends on large, pre-trained structure prediction networks, like RFdiffusion. In contrast, alternative that are trained from scratch, as FrameDiff, still fall short in performance. this context, we introduce Proteus, an innovative deep diffusion network incorporates graph-based triangle methods a multi-track...
Engineered proteins generally must possess a stable structure in order to achieve their designed function. Stable designs, however, are astronomically rare within the space of all possible amino acid sequences. As consequence, many designs be tested computationally and experimentally find ones, which is expensive terms time resources. Here we use high-throughput, low-fidelity assay evaluate stability approximately 200,000 novel proteins. These include wide range sequence perturbations,...
Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic has been widely used for vaccine generation against viruses tumors. However, little known about its structure functional mechanism. Here we determine human ectodomain by cryoelectron microscopy. The shows that 12 extracellular domains form a compact double ring-shaped conformation at acidic pH become extended basic pH. Biochemical data...
We used two approaches to design proteins with shape and chemical complementarity the receptor binding domain (RBD) of SARS-CoV-2 Spike protein near site for human ACE2 receptor. Scaffolds were built around an helix that interacts RBD, or de novo designed scaffolds docked against RBD identify new modes. In both cases, sequences optimized first in silico then experimentally target binding, folding stability. Nine designs bound affinities ranging from 100pM 10nM, blocked bona fide infection...
Significance DEC205 (CD205) is an endocytotic receptor on dendritic cells that recognizes dead in a pH-dependent fashion and has been widely used for vaccine generation immune therapies. However, the physiological ligand(s) of remained unknown decades. Here we identify keratins are cellular ligands human specifically at acidic pH. Keratins structural proteins providing mechanical support tissues. Our results suggest act as markers environments. Moreover, since have diagnostic various tumors,...
Immune receptors have emerged as critical therapeutic targets for cancer immunotherapy. Designed protein binders can high affinity, modularity, and stability hence could be attractive components of therapeutics directed against these receptors, but traditional Rosetta based binder methods using small globular scaffolds difficulty achieving affinity on convex targets. Here we describe the development helical concave tailored to target sites typically involved in immune receptor interactions....
Hepatitis C virus (HCV) is a member of Hepacivirus and belongs to the family Flaviviridae. HCV infects millions people worldwide may lead cirrhosis hepatocellular carcinoma. envelope proteins, E1 E2, play critical roles in viral cell entry act as major epitopes for neutralizing antibodies. However, unlike other known flaviviruses, it has been challenging study proteins E1E2 past decades vitro expressed heterodimers are usually poor quality, making structural functional characterization...
SCARF1 (scavenger receptor class F member 1, SREC-1 or SR-F1) is a type I transmembrane protein that recognizes multiple endogenous and exogenous ligands such as modified low-density lipoproteins (LDLs) important for maintaining homeostasis immunity. But the structural information mechanisms of ligand recognition are largely unavailable. Here, we solve crystal structures N-terminal fragments human SCARF1, which show forms homodimers its epidermal growth factor (EGF)-like domains adopt...
Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by interaction with endogenous ligands. Therapeutic approaches such as LYTAC
CLEC12A, a member of the C-type lectin receptor family involved in immune homeostasis, recognizes MSU crystals released from dying cells. However, molecular mechanism underlying CLEC12A-mediated recognition still remains unclear. Herein, we reported crystal structure human CLEC12A-CTLD and identified unique "basic patch" site on that is necessary for binding crystals. Meanwhile, determined interaction strength between using single-molecule force spectroscopy. Furthermore, found CLEC12A...
Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers single fusions three distinct were designed geometrically match spike (S) trimer architecture optimized by cell-free expression found exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent engage all receptor...
Growth factors and cytokines signal by binding to the extracellular domains of their receptors drive association transphosphorylation receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration how valency geometry affects outcomes, we designed cyclic homo-oligomers with up 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo fibroblast growth-factor (FGFR) module into these...