A5001315246- Protein Structure and Dynamics
- Enzyme Structure and Function
- Signaling Pathways in Disease
- RNA and protein synthesis mechanisms
- Hippo pathway signaling and YAP/TAZ
- Heat shock proteins research
- Cervical Cancer and HPV Research
- Force Microscopy Techniques and Applications
- Genomics and Phylogenetic Studies
- Mass Spectrometry Techniques and Applications
- Virus-based gene therapy research
- Microbial Community Ecology and Physiology
- interferon and immune responses
- vaccines and immunoinformatics approaches
- Hepatitis B Virus Studies
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Phosphodiesterase function and regulation
- Bacteriophages and microbial interactions
- Gut microbiota and health
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Hemoglobin structure and function
- Cellular Mechanics and Interactions
Uppsala University
2013-2024
AstraZeneca (Sweden)
2023-2024
ETH Zurich
2014-2021
Goethe University Frankfurt
2021
Tokyo Metropolitan University
2021
University of Colorado Denver
2021
École Polytechnique Fédérale de Lausanne
2015-2020
Board of the Swiss Federal Institutes of Technology
2014-2017
University of Copenhagen
2008
Inhibition of the ternary protein complex synaptic scaffolding postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and N -methyl- d -aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report design synthesis novel dimeric inhibitor, Tat- PEG4(IETDV) 2 (Tat- -dimer), which binds tandem PDZ1-2 domain PSD-95 with an unprecedented high affinity 4.6 nM, displays extensive...
Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease (APE1) and initiating repair. Here, we describe small molecule (TH10785) that interacts with the phenylalanine-319 glycine-42 amino acids of OGG1, increases enzyme activity 10-fold, generates previously undescribed β,δ-lyase enzymatic function. TH10785 controls catalytic mediated nitrogen base within its molecular structure. In cells, OGG1...
Method20 August 2018Open Access Source DataTransparent process Proteome-wide analysis of phospho-regulated PDZ domain interactions Gustav N Sundell Department Chemistry – BMC, Uppsala University, Uppsala, Sweden Search for more papers by this author Roland Arnold Corresponding Author [email protected] Institute Cancer and Genomic Sciences, College Medical Dental University Birmingham, Edgbaston, UK Muhammad Ali orcid.org/0000-0002-8858-6776 Piangfan Naksukpaiboon Julien Orts Laboratory...
Understanding the molecular principles that govern allosteric communication is an important goal in protein science. One way allostery could be transmitted via sparse energetic networks of residues, and one such evolutionary conserved network was identified PDZ domain family proteins by multiple sequence alignment [Lockless SW, Ranganathan R (1999) Science 286:295–299]. We have reassessed coupling these residues double mutant cycles together with ligand binding stability experiments found...
Protein-protein interactions mediated by modular protein domains are critical for cell scaffolding, differentiation, signaling, and ultimately, evolution. Given the vast number of ligands competing binding to a limited domain families, it is often puzzling how specificity can be achieved. Selectivity may modulated intradomain allostery, whereby remote residue energetically connected functional site via side chain or backbone interactions. Whereas several energetic pathways, which could...
Abstract Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into structurally dynamically correlated sites at atomic resolution. This is demonstrated present work for well-studied PDZ2 domain human tyrosine phosphatase 1E which allostery had been predicted. Two-state were calculated both free form complex with RA-GEF2 peptide using exact nuclear Overhauser effect (eNOE) method. In apo protein, an allosteric...
The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to folded domain. Here, we used proteomic peptide phage display (ProP-PD) identify peptides from the intrinsically regions of human proteome that bind domains encoded by SARS-CoV-2 genome. Eleven proteins were found 281 proteins, and affinities 31 interactions involving eight determined (K
The energy landscape theory provides a general framework for describing protein folding reactions. Because large number of studies, however, have focused on two-state proteins with single well-defined pathways and without detectable intermediates, the extent to which free landscapes are shaped up by native topology at early stages process has not been fully characterized experimentally. To this end, we investigated mechanisms two homologous three-state proteins, PTP-BL PDZ2 PSD-95 PDZ3,...
The protein−protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to C-terminal was used as template finding lead candidates inhibition PSD-95/NMDA interaction. Initially, truncation alanine scan studies were carried out, which resulted in pentapeptide with wild-type affinity, examined fluorescence polarization assay. Further examination performed by...
On the double: Dimerization of monomeric peptide ligands towards PDZ domains protein PSD-95 (postsynaptic density 95) leads to potent inhibitors protein–protein interactions with stability in blood plasma. Optimization length polyethylene glycol linker results unprecedented affinity for PDZ1-2 domain (see picture).
The [Het-s] prion of the fungus Podospora anserina represents a good model system for studying structure-function relationship in amyloid proteins because high resolution solid-state NMR structure form HET-s forming domain (PFD) is available. PFD adopts specific β-solenoid fold with two rungs β-strands delimiting triangular hydrophobic core. A C-terminal loop folds back onto rigid core region and forms more dynamic semi-hydrophobic pocket extending Herein, an alanine scanning mutagenesis was...
Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such emerge evolve on a molecular level. We performed phylogenetic reconstruction, resurrection biophysical characterization of two interacting protein domains, CID NCBD. appeared after the divergence protostomes deuterostomes 450-600 million years ago, while NCBD was present protostome/deuterostome ancestor. The most ancient...
Structural snapshots characterize six hundred million years of evolution intrinsically disordered proteins.
We have recently developed an NMR protocol to extract exact distances between nuclei in proteins from interpretation of NOESY buildup intensities (eNOEs). This enabled us calculate multistate structural ensembles that exhibit realistic spatial sampling and long-range correlations. Our initial studies were laborious required a deep understanding the underlying spin dynamics. Here, we present MatLab package integrates all data processing steps convert assigned peaks series into upper lower...
Conformational selection and induced fit are two well-known mechanisms of allosteric protein−ligand interaction. Some proteins, like ubiquitin, have recently been found to exist in multiple conformations at equilibrium, suggesting that the conformational may be a general mechanism interaction, particular for single-domain proteins. Here, we PDZ2 domain SAP97 binds its ligand via sequential (induced fit) mechanism. We performed binding experiments using peptide ligands observed biphasic...
Intrinsically disordered proteins are very common and mediate numerous protein–protein protein–DNA interactions. While it is clear that these interactions instrumental for the life of mammalian cell, there a paucity data regarding their molecular binding mechanisms. Here we have used short peptides as model system intrinsically proteins. Linear free energy relationships based on rate equilibrium constants to ordered target proteins, PDZ domains, demonstrate native side-chain form mainly...
An important question in protein folding is whether the mechanism sequence dependent and conserved for homologous proteins. In this work we compared kinetic of five p ostsynaptic density protein‐95, d isc‐large tumor suppressor protein, z onula occludens‐1 (PDZ) domains, sharing similar topology but having different primary structures. Investigation proteins under various experimental conditions revealed that kinetics each member PDZ family can be described by a model with two transition...
Abstract For enzyme activity, an exact structural and motional orchestration of the active site its surroundings is believed to be key. In order reveal such possible phenomena at atomic resolution on basis experimental evidence, restraint driven two‐state ensemble prototypical cyclophilin was determined by using a recently introduced NOE approach. The description reveals presence open closed state cyclophilin, which indicative large‐scale correlated motion. state, catalytic preorganized for...
Protein allostery is a phenomenon involving the long range coupling between two distal sites in protein. In order to elucidate at atomic resoluion on ligand-binding WW domain of enzyme Pin1, multistate structures were calculated from exact nuclear Overhauser effect (eNOE). its free form, protein undergoes microsecond exchange states, one which predisposed interact with parent catalytic domain. presence positive allosteric ligand, equilibrium states shifted towards domain-domain interaction,...
A diverse range of pollutants, including heavy metals, agrochemicals, pharmaceutical residues, illicit drugs, personal care products, and other anthropogenic contaminants, pose a significant threat to aquatic ecosystems. The Winam Gulf Lake Victoria, heavily impacted by surrounding human activities, faces potential contamination from these pollutants. However, studies exploring the presence antibiotic resistance genes (ARGs) in lake remain limited. In current study, shotgun metagenomics...