A5057166992- Protein Structure and Dynamics
- Enzyme Structure and Function
- Mass Spectrometry Techniques and Applications
- Nicotinic Acetylcholine Receptors Study
- Ion channel regulation and function
- Pancreatic function and diabetes
- RNA modifications and cancer
- Microbial Metabolic Engineering and Bioproduction
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Bioinformatics and Genomic Networks
- Computational Drug Discovery Methods
- Trypanosoma species research and implications
- Advanced biosensing and bioanalysis techniques
- Cancer Treatment and Pharmacology
- Photoreceptor and optogenetics research
- Ion Transport and Channel Regulation
- PI3K/AKT/mTOR signaling in cancer
- RNA and protein synthesis mechanisms
- Cancer-related molecular mechanisms research
- Cancer Genomics and Diagnostics
- Spectroscopy and Quantum Chemical Studies
- Plant nutrient uptake and metabolism
- interferon and immune responses
- Diverse Applied Research Studies
Karolinska Institutet
2021-2025
Stockholm University
2018-2021
Science for Life Laboratory
2015-2021
KTH Royal Institute of Technology
2015-2019
Universitat Politècnica de Catalunya
2009-2014
Institute for Research in Biomedicine
2010-2014
Barcelona Supercomputing Center
2009-2011
Centro de Investigaciones Biológicas Margarita Salas
2010
Universitat de Barcelona
2009-2010
Abstract The Na + /H exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after /Li linked to pathogenesis of diabetes mellitus and essential hypertension in humans. Despite functional importance structural information molecular basis for its ion-exchange mechanism have been lacking. Here we report cryo-EM structures bison NHA2 detergent nanodiscs, at 3.0 3.5 Å resolution, respectively. structure, together solid-state membrane-based electrophysiology, establishes...
Abstract Protein conformational changes are at the heart of cell functions, from signalling to ion transport. However, transient nature intermediates along transition pathways hampers their experimental detection, making underlying mechanisms elusive. Here we retrieve dynamic information on actual routes principal component analysis (PCA) structurally-rich ensembles and, in combination with coarse-grained simulations, explore landscapes five well-studied proteins. Modelling them as elastic...
Article29 October 2020Open Access Transparent process Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9 Iven Winkelmann Department Biochemistry Biophysics, Stockholm University, Stockholm, Sweden Search for more papers by this author Rei Matsuoka Pascal F Meier Denis Shutin Chemistry, University Oxford, UK Chenou Zhang Physics, Center Biological Arizona State Tempe, AZ, USA Laura Orellana Ricky Sexton Michael Landreh orcid.org/0000-0002-7958-4074 Microbiology,...
FlexServ is a web-based tool for the analysis of protein flexibility. The server incorporates powerful protocols coarse-grained determination dynamics using different versions Normal Mode Analysis (NMA), Brownian (BD) and Discrete Dynamics (DMD). It can also analyze user provided trajectories. allows complete flexibility large variety metrics, including basic geometrical analysis, B-factors, essential dynamics, stiffness collectivity measures, Lindemann's indexes, residue correlation,...
Elastic network models (ENMs) are coarse-grained descriptions of proteins as networks coupled harmonic oscillators. However, despite their widespread application to study collective movements, there is still no consensus parametrization for the ENMs. When compared molecular dynamics (MD) flexibility in solution, ENMs tend disperse important motions into multiple modes. We present here a new ENM, trained against database atomistic MD trajectories. The role residue connectivity, analytical...
Significance EGFR cancer mutations display an astonishing tissue-specific asymmetry: in lung cancer, target the intracellular kinase (KD), while glioblastomas (GBMs), a variety of missense clusters and deletions concentrate at ectodomain (ECD). Intriguingly, GBM-activating share paradoxical preference for inhibitors that bind inactive kinase. By integrating simulations, small-angle X-ray scattering, GBM models, we demonstrate ECD mutants converge to transition state characterized by cryptic...
Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. MGST2 trimer restricts catalysis to only one out three active sites at a time, but the molecular basis is unknown. Here, we present crystal structures human combined with biochemical computational evidence concerted mechanism, involving local unfolding coupled global conformational changes that regulate catalysis....
<title>Abstract</title> Protein conformational changes are the cornerstone of biological function. While conformers captured experimentally represent meta-stable states, pathways connecting them have been elusive for experiments and simulations alike. Nowadays, cryogenic Electron Microscopy is providing rich structural data on proteins trapped in different states increasingly large systems, but these out scope current computational methods, which usually exhibit an...
We present a new method for estimating pathways conformational transitions in macromolecules from the use of discrete molecular dynamics and biasing techniques based on combination essential Maxwell-Demon sampling techniques. The can work with high efficiency at different levels resolution, including atomistic one, help to define initial further exploration by means more accurate simulations. is implemented freely available Web-based application accessible http://mmb.irbbarcelona.org/MDdMD .
Abstract Summary Understanding how proteins transition between different conformers, and conformers relate to each other in terms of structure function, is not trivial. Here, we present an online tool for pathway generation two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts intermediates trapped experimentally. In addition path-generation, the server provides interactive 2D-motion...
EGFR mutations display striking organ-site asymmetry and heterogeneity. We have shown that structurally diverse extracellular mutations, typical of glioblastomas, converge to a similar intermediate conformation, which can be synergistically targeted extra- intracelullarly by antibody mAb806 type-II kinase inhibitors. Our findings reveal convergence behind heterogeneity, paving the way for allostery-based co-targeting.
At the very deepest molecular level, mechanisms of life depend on operation proteins, so-called “workhorses” cell. Proteins are nanoscale machines that transform energy into useful cellular work, such as ion or nutrient transport, information processing, transformation. Behind every biological task, there is a nanometer-sized molecule whose shape and intrinsic motions, binding, sensing properties have been evolutionarily polished for billions years. With emergence structural biology, most...
Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by stature and skeletal changes such as mild spondylar epimetaphyseal affecting primarily the lower limbs. The genetic cause was first reported in 2019 Le Caignec et al., six disease-causing variants gene coding for ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical radiographic data from 12...
Epidermal Growth Factor Receptor (EGFR) signalling is supposed to be triggered by a ligand-induced conformational change of the extracellular domain from closed, self-inhibited tethered monomer, an open untethered state with free dimerization arm. The ectodomain also untethers spontaneously, but molecular mechanism still unknown. Experiments mAb806 antibody have suggested existence third state, uncharacterised, appearing transiently during transition, and which exposes cryptic epitope hidden...
Pentameric ligand-gated ion channels (PLGICs) are a family of proteins that convert chemical signals into fluxes through cellular membranes. Their structures highly conserved across all kingdoms from bacteria to eukaryotes. Beyond their classical roles in neurotransmission and neurological disorders, PLGICs have been recently related cell proliferation cancer. Here, we focus on the best characterized eukaryotic channel, glycine receptor (GlyR), investigate its mutational patterns...