A5084075339- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Neuroscience and Neuropharmacology Research
- Protein Structure and Dynamics
- Bioinformatics and Genomic Networks
- Mass Spectrometry Techniques and Applications
- Neuroscience and Neural Engineering
- Ion channel regulation and function
- Chemical Synthesis and Analysis
- Advanced Fluorescence Microscopy Techniques
- Biochemical and Structural Characterization
- Advanced Electron Microscopy Techniques and Applications
- Photoreceptor and optogenetics research
- Simulation Techniques and Applications
- Computational Drug Discovery Methods
- Photosynthetic Processes and Mechanisms
- Advanced Data Processing Techniques
- Advanced Memory and Neural Computing
- Glycosylation and Glycoproteins Research
- Spectroscopy and Quantum Chemical Studies
- Monoclonal and Polyclonal Antibodies Research
- Nicotinic Acetylcholine Receptors Study
- Cellular transport and secretion
- Neural dynamics and brain function
Utrecht University
2019-2024
Stanford University
2019-2023
École Polytechnique Fédérale de Lausanne
2016-2021
University of Basel
2017-2018
University of Geneva
2017-2018
University of Zurich
2017-2018
An emerging class of therapeutic molecules are cyclic peptides with over 40 peptide drugs currently in clinical use. Their mode action is, however, not fully understood, impeding rational drug design. Computational techniques could positively impact their design, but modeling them and interactions remains challenging due to nature flexibility. This study presents a step-by-step protocol for generating conformations docking protein target using HADDOCK2.4. A dataset 30 peptide-protein...
Hv1s are ubiquitous highly selective voltage-gated proton channels involved in male fertility, immunology, and the invasiveness of certain forms breast cancer. The mechanism extrusion Hv1 is not yet understood, while it constitutes first step toward design high-affinity drugs aimed at this important pharmacological target. In contribution, we explore details via an integrative approach, using classical QM/MM molecular dynamics simulations a monomeric hHv1 model. We propose that protons...
Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor reinforcement learning. Strengthening the corticostriatal synapses depends on second messenger cAMP, whose synthesis catalysed by enzyme adenylyl cyclase 5 (AC5), which itself regulated stimulatory Gαolf inhibitory Gαi proteins. AC isoforms have been suggested act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close time. However, mechanism...
G proteins are part of the G-protein-coupled receptor (GPCR) signal transduction cascade in which they transfer a from membrane-embedded GPCR to other cell. In case inhibitory G-protein heterotrimer, permanent N-terminal myristoylation can transiently localize Gαi subunit at membrane as well crucially influence Gαi's function GTP-bound conformation. The attachment lipids is known be essential for trafficking; however, our results suggest that lipidation also important protein-protein...
Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled-receptor signal transduction pathways, which a well-known target for drug development. AC regulated by activated stimulatory (Gαs) and inhibitory (Gαi) G proteins the cytosol. Although experimental studies have shown that these Gα subunits can stimulate or inhibit AC's function non-competitive way, it not well understood what difference their mode of action as both appear structurally very similar non-lipidated...
Abstract Neuronal spiking activity is routinely recorded using genetically encoded calcium indicators (GECIs), but imaging limited in temporal resolution and does not report subthreshold voltage changes. Genetically (GEVIs) offer better sensitivity, spike detection with fast GEVIs has required specialized equipment. Here, we the ASAP4 subfamily of that brighten response to membrane depolarization, inverting fluorescence-voltage relationship previous ASAP GEVIs. Two variants, ASAP4b ASAP4e,...
Adenylyl cyclase (AC) generates cyclic AMP required for a variety of cellular functions, and its regulation plays major role in signal transduction eukaryotes prokaryotes. All membrane-bound AC isoforms can be activated by stimulatory G-proteins, but only AC1, AC5, AC6 both stimulated inhibited active Gα subunits, Gαs Gαi, respectively. In principle, these Gαi-sensitive could form binary ternary complexes with subunits due to the noncompetitive association inhibitory Gα. However, formation...
A wide range of cellular processes requires the formation multimeric protein complexes. The rise cryo-electron microscopy (cryo-EM) has enabled structural characterization these assemblies. density maps produced can, however, still suffer from limited resolution, impeding process resolving structures at atomic resolution. In order to solve this issue, monomers can be fitted into low- medium-resolution maps. Unfortunately, models frequently contain clashes protein-protein interfaces (PPIs),...
Rhodopsin is a photoactive G-protein-coupled receptor (GPCR) that converts dim light into signal for the brain, leading to eyesight. Full activation of this GPCR achieved after passing through several steps protein's photoactivation pathway. Key events rhodopsin are initial cis-trans photoisomerization covalently bound retinal moiety followed by conformational rearrangements and deprotonation chromophore's protonated Schiff base (PSB), which ultimately lead full in meta II state. PSB crucial...
Abstract Adenylyl cyclases (ACs) play a key role in many signaling cascades. ACs catalyze the production of cyclic AMP from ATP and this function is stimulated or inhibited by binding their cognate stimulatory inhibitory Gα subunits, respectively. Here we used simulation tools to uncover molecular subcellular mechanisms AC function, with focus on AC5 isoform, extensively studied experimentally. First, quantum mechanical/molecular mechanical free energy simulations were investigate enzymatic...
Conversion of adenosine triphosphate (ATP) to the second messenger cyclic monophosphate (cAMP) is an essential reaction mechanism that takes place in eukaryotes, triggering a variety signal transduction pathways. ATP conversion catalyzed by enzyme adenylyl cyclase (AC), which can be regulated binding inhibitory, G α i , and stimulatory, s subunits. In past twenty years, several crystal structures AC isolated form complexed subunits have been resolved. Nevertheless, molecular basis inhibition...
The HADDOCK team participated in CAPRI rounds 47-55 as both server, manual predictor, and scorers. Throughout these rounds, we used a plethora of computational strategies to predict the structure protein complexes. Of 10 targets comprising 24 interfaces, achieved acceptable or better models for 3 human category 1 server category. Our performance scoring challenge was slightly better, with our simple protocol being only one capable identifying an model Target 234. This result highlights...
ABSTRACT The HADDOCK team participated in CAPRI rounds 47–55 as server, manual predictor, and scorers. Throughout these rounds, we used a plethora of computational strategies to predict the structure protein complexes. Of 10 targets comprising 24 interfaces, achieved acceptable or better models for 3 human category 1 server category. Our performance scoring challenge was slightly better, with our simple protocol being only one capable identifying an model Target 234. This result highlights...
Abstract Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor reinforcement learning. Strengthening the corticostriatal synapses depends on second messenger cAMP, whose synthesis catalysed by enzyme adenylyl cyclase 5 (AC5), which itself regulated stimulatory Gα olf inhibitory i proteins. AC isoforms have been suggested act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close time. However,...
The steep rise in protein sequences and structures has paved the way for bioinformatics approaches to predict residue-residue interactions complexes. Multiple sequence alignments are commonly used contact predictions identify co-evolving residues. These contacts, however, often include false positives (FPs), which may impair their use three dimensional of biomolecular complexes affect accuracy generated models. Previously, we have developed DisVis FP mass spectrometry cross-linking data....
Abstract An emerging class of therapeutic molecules are cyclic peptides with over 40 peptide drugs currently in clinical use. Their mode action is, however, not fully understood, impeding rational drug design. Computational techniques could positively impact their design but modeling them and interactions remains challenging due to nature flexibility. This study presents a step-by-step protocol for generating conformations docking protein target using HADDOCK2.4. A dataset 30 peptide-protein...
GRK5 belongs to a family of G protein‐coupled receptor (GPCR) kinases that mediate phosphorylation and desensitization GPCRs. In addition, has been implicated in number diseases through its ability phosphorylate non‐receptor substrates such as α‐synuclein, HDAC5 moesin. is directly regulated by the calcium‐sensing protein calmodulin (CaM). Ca 2+ /CaM binds inhibits GPCR phosphorylation, though precise mechanism regulation unclear. Interestingly, retains kinase activity when complex with CaM....
ABSTRACT The steep rise in available protein sequences and structures has paved the way for bioinformatics approaches to predict residue-residue interactions complexes. Multiple sequence alignments are commonly used intermolecular contact predictions identify co-evolving residues. These contacts, however, often include false positives (FPs), which may impair their use three dimensional of biomolecular complexes affect accuracy generated models. Previously, we have developed DisVis positive...
Abstract A wide range of cellular processes require the formation multimeric protein complexes. The rise cryo-electron microscopy (cryo-EM) has enabled structural characterization these assemblies. produced density maps can, however, still suffer from limited resolution, impeding process resolving structures at atomic resolution. In order to solve this issue, monomers can be fitted into low-to-medium resolution maps. Unfortunately, models frequently contain clashes protein-protein interfaces...