A5062435076- Ion channel regulation and function
- ATP Synthase and ATPases Research
- Ion Transport and Channel Regulation
- Lipid metabolism and disorders
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Cardiac electrophysiology and arrhythmias
- Mitochondrial Function and Pathology
- Enzyme function and inhibition
- Trace Elements in Health
- Neuroscience and Neuropharmacology Research
- Natural product bioactivities and synthesis
- Plant biochemistry and biosynthesis
- Pneumocystis jirovecii pneumonia detection and treatment
- Antifungal resistance and susceptibility
- Drug Transport and Resistance Mechanisms
- Sesquiterpenes and Asteraceae Studies
- Adenosine and Purinergic Signaling
- Caveolin-1 and cellular processes
- Traditional and Medicinal Uses of Annonaceae
- DNA Repair Mechanisms
- Biochemical and Molecular Research
- Cardiovascular Function and Risk Factors
- Marine Sponges and Natural Products
- Protein Kinase Regulation and GTPase Signaling
- Cancer therapeutics and mechanisms
University of Copenhagen
2019-2023
Rigshospitalet
2021-2023
Copenhagen University Hospital
2023
Aarhus University
2004-2013
Danish National Research Foundation
2007-2010
James Madison University
2007
The first crystal structure of the neurotransmitter/sodium symporter homolog LeuT revealed an occluded binding pocket containing leucine and 2 Na(+); later structures showed tricyclic antidepressants (TCAs) in extracellular vestibule approximately 11 A above bound Na(+). We recently found this region to be a second (S2) site that substrate triggers Na(+)-coupled symport. Here, we show profound inhibitory effect n-octyl-beta-d-glucopyranoside (OG), detergent used for crystallization, on S2...
Thapsigargin (Tg), a specific inhibitor of sarco/endoplasmic Ca2+-ATPases (SERCA), binds with high affinity to the E2 conformation these ATPases. SERCA inhibition leads elevated calcium levels in cytoplasm, which turn induces apoptosis. We present x-ray crystallographic and intrinsic fluorescence data show how Tg chemical analogs compound modified or removed side chains bind isolated 1a membranes. This occurs by uptake via membrane lipid followed insertion into resident intramembranous...
Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT chloride-independent but contain an acidic residue (Glu290 LeuT) at site where eukaryotic have serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, cocrystallized with bromide or chloride, the anion is coordinated side chain hydroxyls from Tyr47, Ser290, and Thr254 amide...
The complex between lipoprotein lipase (LPL) and its endothelial receptor (GPIHBP1) is responsible for the lipolytic processing of triglyceride-rich lipoproteins (TRLs) along capillary lumen, a physiologic process that releases lipid nutrients vital organs such as heart skeletal muscle. LPL activity regulated in tissue-specific manner by endogenous inhibitors (angiopoietin-like [ANGPTL] proteins 3, 4, 8), but molecular mechanisms are incompletely understood. ANGPTL4 catalyzes inactivation...
The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery dietary lipids to heart, skeletal muscle, and adipose tissue. TRLs LPL regulated in a tissue-specific manner complex interplay between activators inhibitors. Angiopoietin-like protein 4 (ANGPTL4) inhibits reducing its thermal stability catalyzing irreversible unfolding LPL's α/β-hydrolase domain. We previously mapped ANGPTL4 binding site on defined downstream events...
ABSTRACT The plasma membrane H + -ATPase (Pma1) is an essential fungal protein and a proposed target for new antifungal medications. compounds in small-molecule library containing ∼191,000 commercially available were screened their ability to inhibit Saccharomyces cerevisiae membranes Pma1. overall hit rate was 0.2%, corresponding 407 compounds. These further evaluated ATPase selectivity broad-spectrum activity. Following this work, one Pma1 inhibitor series based on compound 14 analogs...
GPIHBP1, an endothelial cell (EC) protein, captures lipoprotein lipase (LPL) within the interstitial spaces (where it is secreted by myocytes and adipocytes) transports across ECs to its site of action in capillary lumen. GPIHBP1's 3-fingered LU domain required for LPL binding, but function acidic (AD) has remained unclear. We created mutant mice lacking AD found severe hypertriglyceridemia. As expected, GPIHBP1 retained capacity bind LPL. Unexpectedly, however, most was located on abluminal...
K+ plays an important role for the function of sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA), but its binding site within molecule has remained unidentified. We have located a ion in P-domain by means x-ray crystallography using crystals prepared presence congener Rb+. Backbone carbonyls from loop containing residues 711-715 together with side chain Glu732 define K+/Rb+ conformation bound Ca2+, ADP, and AlF4-. Functional analysis mutants alterations to shows that this is indeed...
ABSTRACT An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well resistance to currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism action. Here we report identification and characterization two zinc-attenuating compounds, ZAC307 ZAC989, which exhibit vitro activity vivo efficacy kidney burden candidiasis model. The compounds were identified serendipitously part drug discovery process aimed at finding inhibitors...
In recent years crystal structures of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1a), stabilized in various conformations with nucleotide and phosphate analogs, have been obtained. However, structural analysis mutant forms would also be valuable to address key mechanistic aspects. We worked out a procedure for affinity purification SERCA1a heterologously expressed yeast cells, producing sufficient amounts crystallization biophysical studies. present here two forms, D351A P312A, issue...
Crude extracts of 33 plant species were assessed for fungal plasma membrane (PM) H(+)-ATPase inhibition. This led to identification 18 showing more than 95% inhibition at a concentration 7.5 mg/mL and/or concentration-dependent activity profile. These selected semi-high-resolution PM screening, and, on the basis these results, Haplocoelum foliolosum (Hiern) Bullock and Sauvagesia erecta L. investigation by high-resolution screening. Structural analysis performed high-performance liquid...
Compounds belonging to a carbazole series have been identified as potent fungal plasma membrane proton adenosine triphophatase (H+-ATPase) inhibitors with broad spectrum of antifungal activity. The compounds inhibit the triphosphate (ATP) hydrolysis activity essential H+-ATPase, thereby functionally inhibiting extrusion protons and extracellular acidification, processes that are responsible for maintaining high potential. compound class binds inhibits H+-ATPase within minutes, leading death...
We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using set rationally designed analogues, we analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. found that inhibit adenosine triphosphate (ATP) hydrolysis the fungal H+-ATPase, depolarize plasma membrane exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate many also mammalian Ca2+-ATPase (SERCA)...