A5059183000- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- vaccines and immunoinformatics approaches
- Protein Structure and Dynamics
- CAR-T cell therapy research
- Spondyloarthritis Studies and Treatments
- RNA Research and Splicing
- Glycosylation and Glycoproteins Research
- Cancer Immunotherapy and Biomarkers
- Diabetes and associated disorders
- Advanced Proteomics Techniques and Applications
- Peptidase Inhibition and Analysis
- Toxoplasma gondii Research Studies
- Ubiquitin and proteasome pathways
- Galectins and Cancer Biology
- Genomics and Chromatin Dynamics
- Plant Virus Research Studies
- Fluorine in Organic Chemistry
- Inflammatory Bowel Disease
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Machine Learning in Bioinformatics
- Antimicrobial Peptides and Activities
Freie Universität Berlin
2018-2024
Ain Shams University
2014-2024
Laboratoire de Biochimie
2021
QB3
2017-2018
University of California, Berkeley
2017-2018
Constructor University
2013-2015
The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated virtual screening performance of 37 common drug targets, each with AF2 and known holo apo DUD-E data set. In a subset 27 targets where are suitable for refinement, show comparable early enrichment active compounds (avg. EF 1%: 13.0)...
Abstract Understanding and control of structures rates involved in protein ligand binding are essential for drug design. Unfortunately, atomistic molecular dynamics (MD) simulations cannot directly sample the excessively long residence rearrangement times tightly complexes. Here we exploit recently developed multi-ensemble Markov model framework to compute full protein-peptide kinetics oncoprotein fragment 25–109 Mdm2 nano-molar inhibitor peptide PMI. Using this system, report, first time,...
The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which correlated to the binding high-affinity antigenic peptide ligands. To investigate molecular features MHC-I these detect, we have followed hypothesis suboptimally loaded are characterized conformational mobility in F pocket region site. We created a novel variant an protein, Kb-Y84C, two alpha helices this...
The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid the F pocket of peptide-binding groove. To understand how this unique difference leads to different behavior proteins cell, we have investigated conformational stability both using combination silico and experimental approaches. Here, show that binding site B*27:05 conformationally disordered absence peptide due charge repulsion at bottom...
T cell receptor (TCR) recognition of antigenic peptides bound and presented by class I major histocompatibility complex (MHC) proteins underlies the cytotoxic immune response to diseased cells. Crystallographic structures TCR-peptide/MHC complexes have demonstrated how TCRs simultaneously interact with both peptide MHC protein. However, it is increasingly recognized that, beyond serving as a static platform for presentation, physical properties are tuned different in ways that not always...
Abstract Presentation of antigenic peptides by major histocompatibility complex class II (MHC-II) proteins determines T helper cell reactivity. The MHC-II genetic locus displays a large degree allelic polymorphism influencing the peptide repertoire presented resulting protein allotypes. During antigen processing, human leukocyte (HLA) molecule HLA-DM (DM) encounters these distinct allotypes and catalyzes exchange placeholder CLIP exploiting dynamic features MHC-II. Here, we investigate 12...
The Major Histocompatibility Complex of Class II (MHCII) immunopeptidome represents the repertoire antigenic peptides with potential to activate CD4+ T cells. An understanding how relative abundance specific epitopes affects outcome cell responses is an important aspect adaptive immunity, and offers a venue more rationally tailor activation in context disease. Recent advances mass spectrometric instrumentation, computational power, labelling strategies, software analysis have enabled...
The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored ER-resident peptide loading (PLC), which contains exchange catalyst tapasin. Tapasin stabilizes MHC-I and promotes formation stable peptide-MHC-I (pMHC-I) complexes that serve as T antigens. Exchange suboptimal high-affinity ligands catalyzed tapasin, but underlying mechanism still elusive. Here we analyze tapasin-induced changes in dynamics, find to exploit two...
Major histocompatibility complex (MHC) class I molecules (proteins) bind peptides of eight to ten amino acids present them at the cell surface cytotoxic T cells. The binding groove binds peptide via hydrogen bonds with termini and diverse interactions anchor residue side chains peptide. To elucidate which these is most important for thermodynamic kinetic stability peptide-bound state, we have combined molecular dynamics simulations experimental approaches in an investigation conformational...
BackgroundPathogenic variants in STXBP1/Munc18-1 cause severe encephalopathies that are among the most common genetic neurodevelopmental disorders. Different molecular disease mechanisms have been proposed and pathogenicity prediction is limited. This study aims to define a generalized concept for STXBP1-related disorders improve prediction.MethodsA cohort of 11 disease-associated five neutral (detected healthy individuals) was tested three cell-free assays, heterologous cells primary...
Abstract Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark mediated immunity. Recent data suggest that variations in TCR binding geometry may influence signaling, which could help explain outliers relationships between physical parameters such as TCR‐pMHC affinity and function. Traditionally, has been described with simple descriptors the crossing angle, quantifies what become known TCR's diagonal mode....
The immunogenicity of H ‐2 D b ( ) restricted epitopes can be significantly increased by substituting peptide position 3 to a proline (p3 P ). p3 modification enhances MHC stability without altering the conformation modified epitope allowing for T ‐cell cross‐reactivity with native peptide. present study reveals how specific interactions between and highly conserved heavy chain residue Y 159 increase in complex an optimized version melanoma‐associated gp100 25–33 . Furthermore, directly...
The question whether interference with the ubiquitous splicing machinery can lead to cell-type specific perturbation of cellular function is addressed here by T cell ablation general U5 snRNP assembly factor CD2BP2/U5-52K. This protein defines family nuclear GYF domain containing proteins that are ubiquitously expressed in eukaryotes essential functions ascribed early embryogenesis and organ function. Abrogating CD2BP2/U5-52K cells, allows us delineate consequences interferences for...
HLA-B*27:05 is associated with the development of autoimmune spondyloarthropathies, but precise causal relationship between MHC haplotype and disease pathogenesis yet to be elucidated. Studies focusing on structure cellular trafficking implicate several links onset inflammation unusual conformations molecule inside at surface antigen presenting cells. Several lines evidence emphasize emergence those unnatural protein under conditions where peptide loading onto B*27:05 impaired. To understand...
Neoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment immune checkpoint inhibitors. are therefore highly attractive targets for the development of approaches in personalized medicine, although many aspects their quality and associated not yet well understood. In a case study metastatic malignant melanoma, we aimed to perform an in-depth characterization neoantigens respective T-cell context modulation. Three neoantigens, which identified either...
The anterograde transport of secretory proteins from the endoplasmic reticulum ( ER ) to plasma membrane is a multi‐step process. Secretory differ greatly in their rates cell surface, but contribution each individual step this difference poorly understood. Transport may be determined by protein folding, chaperone association , access exit sites ERES and retrieval ‐Golgi intermediate compartment or cis . We have used combination folding trafficking assays identify differential surface two...
Identifying T cell epitopes is essential for studying and potentially tuning immune responses to pathogens. The polymorphic nature of major histocompatibility complex class II (MHCII)-genes, the complexity antigen processing mechanisms hinders effective prediction immunodominant patterns in humans, specially at population level. Here, we combined output a reconstituted system silico tools SARS-CoV-2 antigens considering broad-population coverage DRB1* panel gain insights on immunodominance...
Abstract Neoantigens derived from somatic mutations have been demonstrated to correlate with therapeutic responses mediated by treatment immune checkpoint inhibitors. are therefore highly attractive targets for the development of personalized medicine approaches although their quality and associated is not yet well understood. In a case study metastatic malignant melanoma, we performed an in-depth characterization neoantigens respective T-cell in context immunotherapy Ipilimumab. Three...