A5058775657- Ion channel regulation and function
- Ion Transport and Channel Regulation
- T-cell and B-cell Immunology
- Membrane-based Ion Separation Techniques
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Ion Channels and Receptors
- RNA and protein synthesis mechanisms
- Neuropeptides and Animal Physiology
- Mycobacterium research and diagnosis
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Veterinary medicine and infectious diseases
- Mass Spectrometry Techniques and Applications
- Cardiac electrophysiology and arrhythmias
- Toxin Mechanisms and Immunotoxins
- bioluminescence and chemiluminescence research
- Cancer Immunotherapy and Biomarkers
- Diabetes and associated disorders
- Nicotinic Acetylcholine Receptors Study
- CAR-T cell therapy research
- Protein Structure and Dynamics
- Pharmacological Effects of Natural Compounds
University of Oxford
2019-2025
Genomics (United Kingdom)
2019-2020
Discovery Centre
2020
University of Copenhagen
2017-2018
Lund University
2012-2016
University of Padua
2012
Veneto Institute of Molecular Medicine
2012
University of Gothenburg
2010
GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding GPCR conformational regulation by different ligands. Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between conformations. To address this deficit, we generated samples a wild-type (A2AR) that are deuterated apart from 1H/13C NMR probes at isoleucine δ1 methyl groups, which facilitated TROSY measurements with opposing Our data indicate low...
Abstract Superantigens are immune-stimulatory toxins produced by Staphylococcus aureus, which able to interact with host immune receptors induce a massive release of cytokines, causing toxic shock syndrome and possibly death. In this article, we present the x-ray structure staphylococcal enterotoxin B (SEB) in complex its receptors, TCR MHC class II, forming ternary complex. The structure, combination functional analyses, clearly shows how SEB adopts wedge-like position when binding β-chain...
Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling electrical activity many different cell types and represent attractive therapeutic targets. However, identification highly selective small molecule drugs against these has been challenging due to high degree structural functional conservation that exists not only between K2P channels, but across whole K+ channel superfamily. To address issue selectivity, here we generate camelid...
The TREK subfamily of two-pore domain K+ (K2P) channels are inhibited by fluoxetine and its metabolite, norfluoxetine (NFx). Although not the principal targets this antidepressant, channel inhibition NFx has provided important insights into conformational changes associated with gating highlighted role selectivity filter in process. However, despite availability TREK-2 crystal structures bound, precise mechanisms underlying remain elusive. previously been proposed to be a state-dependent...
Abstract Sleep apnea is a common disorder that represents global public health burden. KCNK3 encodes TASK-1, K + channel implicated in the control of breathing, but its link with sleep remains poorly understood. Here we describe new developmental associated (developmental delay apnea, or DDSA) caused by rare de novo gain-of-function mutations . The cluster around ‘X-gate’, gating motif controls opening, and produce overactive channels no longer respond to inhibition G-protein-coupled...
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders, example Alzheimer’s disease amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16-Å-resolution cryo-EM structure human that reveals several distinct...
The T lymphocytes are the most important effector cells in immunotherapy of cancer. conceptual objective for developing tumor targeted superantigen (TTS) ABR-217620 (naptumomab estafenatox, 5T4Fab-SEA/E-120), now phase 3 studies advanced renal cell cancer, was to selectively coat with cytotoxic (CTL) target structures functionally similar natural CTL pMHC molecules. Here we present data showing that molecular basis anti-tumor activity by resides distinct interaction between receptor β...
Abstract Superantigens are toxins produced by Staphylococcus aureus, called staphylococcal enterotoxins (abbreviated SEA to SEU). They can cross-link the T cell receptor (TCR) and major histocompatibility complex class II, triggering a massive activation hence disease. Due high stability toxicity, superantigens potential agents of bioterrorism. Hence, antagonists may not only be useful in treatment disease but also serve as countermeasures biological warfare. Of particular interest...
T cells are crucial players in cell-mediated immunity. The specificity of their receptor, the cell receptor (TCR), is central for immune system to distinguish foreign from host antigens. Superantigens bacterial toxins capable inducing a toxic response by cross-linking TCR and major histocompatibility complex (MHC) class II circumventing antigen specificity. Here, we present structure staphylococcal enterotoxin E (SEE) with human as well unligated structure. There clear structural changes...
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic lipid-activated Two-Pore Domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders such as Alzheimer’s Amyothropic Lateral Sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16 Å resolution cryoEM structure human that reveals several unique features,...
Abstract Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18 , play crucial roles in controlling electrical activity many different cell types and represent attractive therapeutic targets. However, identification highly selective small molecule drugs against these has been challenging due to high degree structural functional conservation that exists not only between K2P channels, but across whole K + channel superfamily. To address issue selectivity, we generated camelid...
TASK channels are unusual members of the two-pore domain potassium (K 2P ) channel family, with unique and unexplained physiological pharmacological characteristics. TASKs found in neurons 1,2 , cardiomyocytes 3–5 vascular smooth muscle cells 6 where they involved regulation heart rate 7 pulmonary artery tone 6,8 sleep/wake cycles 9 responses to volatile anaesthetics 9–12 . K regulate resting membrane potential, providing background + currents controlled by numerous stimuli 13,14 Unlike...
Abstract TASK-1 and TASK-3 are pH-sensitive Two-Pore Domain (K2P/ KCNK ) K + channels. Their functional roles make them promising targets for the treatment of multiple disorders including sleep apnea, pain atrial fibrillation. Rare genetic mutations in these channels also associated with neurodevelopmental hypertensive disorders. A recent crystal structure revealed a lower ‘X-gate’ that is hotspot missense gain-of-function DDSA (Developmental Delay Sleep Apnea). However, structural basis...
ABSTRACT The TREK subfamily of Two-Pore Domain (K2P) K + channels are inhibited by fluoxetine and its metabolite, norfluoxetine (NFx). Although not the principal targets this antidepressant, channel inhibition NFx has provided important insights into conformational changes associated with gating highlighted role selectivity filter in process. But despite availability TREK-2 crystal structures bound, precise mechanisms underlying remain elusive. previously been proposed to be a...
Abstract Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, modulates neurotransmission and regulates kinetics of signaling proteins. To understand structural basis proline import, we solved structure transporter SIT1 complex COVID-19 viral receptor ACE2 by cryo-electron microscopy. The pipecolate-bound reveals specific sequence requirements for transport SLC6 family how this excludes acids extended side...