A5006480282- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- RNA modifications and cancer
- Computational Drug Discovery Methods
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Photoreceptor and optogenetics research
- Mass Spectrometry Techniques and Applications
- Neuroscience and Neuropharmacology Research
- Protein Structure and Dynamics
- Genomics and Phylogenetic Studies
- Chemical synthesis and alkaloids
- Pharmacological Effects and Assays
- bioluminescence and chemiluminescence research
- Genomics and Rare Diseases
- Pharmacological Receptor Mechanisms and Effects
- Machine Learning in Materials Science
- Alkaloids: synthesis and pharmacology
- Microbial Natural Products and Biosynthesis
- Chromosomal and Genetic Variations
- Neuroscience and Neural Engineering
- Synthesis and Reactions of Organic Compounds
- Nicotinic Acetylcholine Receptors Study
- Asthma and respiratory diseases
- Plant biochemistry and biosynthesis
Stanford University
2017-2024
Laboratoire d'Informatique de Paris-Nord
2020
Massachusetts Institute of Technology
2016-2018
Moscow Institute of Thermal Technology
2017
ChRmine, a recently discovered pump-like cation-conducting channelrhodopsin, exhibits puzzling properties (large photocurrents, red-shifted spectrum, and extreme light sensitivity) that have created new opportunities in optogenetics. ChRmine its homologs function as ion channels but, by primary sequence, more closely resemble pump rhodopsins; mechanisms for passive channel conduction this family remained mysterious. Here, we present the 2.0 Å resolution cryo-EM structure of revealing...
Abstract The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As most G protein-coupled receptors (GPCRs), however, the molecular mechanisms ligand-specific at have remained unclear. To better understand determinants bias, we apply structure determination, atomic-level dynamics (MD) simulations,...
The >800 human G protein–coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state- and the largest class of drug targets. Their myriad structural conformations various modes signaling make it challenging understand their structure function. Here, we developed a platform characterize large libraries GPCR variants in lines with barcoded transcriptional reporter protein signal transduction. We tested 7800 7828 possible single amino acid...
KCR channelrhodopsins (K
Experimental detection of RNA splicing branchpoints is difficult. To date, high-confidence experimental annotations exist for 18% 3′ splice sites in the human genome. We develop a deep-learning-based branchpoint predictor, LaBranchoR, which predicts correct at least 75% genome-wide. Detailed analysis cases our predicted deviates from data suggests over 90% cases. use to identify novel sequence element upstream consistent with extended U2 snRNA base-pairing, show an association between weak...
A pervasive challenge in drug design is determining how to expand a ligand─a small molecule that binds target biomolecule─in order improve various properties of the ligand. Adding single chemical groups, known as fragments, important for lead optimization tasks, and adding multiple fragments critical fragment-based design. We have developed comprehensive framework uses machine learning three-dimensional protein–ligand structures address this challenge. Our method, FRAME, iteratively...
Significance Structure-based drug design depends on the ability to predict both three-dimensional structures of candidate molecules bound their targets and associated binding affinities. We demonstrate that one can substantially improve accuracy these predictions using easily obtained data about completely different bind same target without requiring any target-bound molecules. The approach we developed integrate physical data-driven modeling may find a variety applications in rapidly...
Spliced messages constitute one-fourth of expressed mRNAs in the yeast Saccharomyces cerevisiae, and most metazoans. Splicing requires 5' splice site (5'SS), branch point (BP), 3' (3'SS) elements, but role BP splicing control is poorly understood because identification remains difficult. We developed a high-throughput method, Branch-seq, to map BPs 5'SSs isolated RNA lariats. Applied S. Branch-seq detected 76% expressed, annotated identified comparable number novel BPs. performed RNA-seq...
Abstract Rapid advances in next-generation sequencing technologies have dramatically changed our ability to perform genome-scale analyses of human genomes. The reference genome used for most genomic represents only a small number individuals, limiting its usefulness genotyping. We designed novel method, HISAT-genotype, representing and searching an expanded model the genome, which comprehensive catalogue known variants haplotypes is incorporated into data structure alignment. This strategy...
Recursive splicing, a process by which single intron is removed from pre-mRNA transcripts in multiple distinct segments, has been observed small subset of Drosophila melanogaster introns. However, detection recursive splicing requires observation intermediates that are inherently unstable, making it difficult to study. Here we developed new computational approaches identify recursively spliced introns and applied them, combination with existing methods, nascent RNA sequencing data S2 cells....
Abstract The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling G-protein-coupled receptors (GPCRs), largest class drug targets. Decades research have widely accepted view that all agonists—ligands trigger GPCR activation—function by causing rearrangement GPCR’s transmembrane helices, opening an intracellular pocket for binding transducer proteins. Here we demonstrate certain...
Abstract In humans, the 813 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and largest class of drug targets. Their myriad structural conformations various modes signaling make it challenging understand their structure function. Here we developed a platform characterize large libraries GPCR variants in human lines with barcoded transcriptional reporter G-protein signal transduction. We tested 7,800 7,828 possible single amino...
Abstract Experimental detection of RNA splicing branchpoints, the nucleotide serving as nucleophile in first catalytic step splicing, is difficult. To date, annotations exist for only 16-21% 3’ splice sites human genome and even these limited have been shown to be plagued by noise. We develop a sequence-only, deep learning based branchpoint predictor, LaBranchoR, which we conclude predicts correct over 90% genome-wide. Our predicted branchpoints show large agreement with trends observed raw...
Summary ChRmine 1 , a recently-discovered bacteriorhodopsin-like cation-conducting channelrhodopsin 1, 2 exhibits puzzling properties (unusually-large photocurrents, exceptional red-shift in action spectrum, and extreme light-sensitivity) that have opened up new opportunities optogenetics 3–5 . its homologs function as light-gated ion channels, but by primary sequence more closely resemble pump rhodopsins; the molecular mechanisms for passive channel conduction this family of proteins, well...
Abstract Drugs targeting the G protein-coupled μ-opioid receptor (μOR) are most effective analgesics available but also associated with fatal respiratory depression. While some partial opioid agonists appear to be safer than full agonists, signaling pathways responsible for depression have yet elucidated. Here we investigated structural and mechanistic basis of action lofentanil (LFT) mitragynine pseudoindoxyl (MP), two μOR different safety profiles. LFT, one potent lethal opioids, MP, a...
Abstract There are over 15,000 known variants that cause human inherited disease by disrupting RNA splicing. While several in silico methods such as CADD, EIGEN and LINSIGHT commonly used to predict the pathogenicity of noncoding variants, we introduce S-CAP, a tool developed specially for splicing which is better able effectively distinguish pathogenic splicing-relevant from benign variants. S-CAP novel predictor reduces number uncertain significance patient exomes 41%, nearly 3-fold...