A5048923951- Photosynthetic Processes and Mechanisms
- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Porphyrin and Phthalocyanine Chemistry
- Genomics and Rare Diseases
- Viral Infections and Outbreaks Research
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Genomics and Phylogenetic Studies
- RNA and protein synthesis mechanisms
- Hemoglobin structure and function
- Spectroscopy and Quantum Chemical Studies
- Computational Drug Discovery Methods
- Wnt/β-catenin signaling in development and cancer
- Genetic Neurodegenerative Diseases
- Synthesis and Biological Evaluation
- Skin and Cellular Biology Research
- vaccines and immunoinformatics approaches
- Research on Leishmaniasis Studies
- Surface Chemistry and Catalysis
- Epigenetics and DNA Methylation
- Contact Dermatitis and Allergies
- Metal-Catalyzed Oxygenation Mechanisms
- 14-3-3 protein interactions
- Mass Spectrometry Techniques and Applications
University of Dundee
2015-2024
National University of Ireland, Maynooth
2023
Trinity College Dublin
2011-2016
Trinity College
2015
University College Dublin
2015
St. James's Hospital
2011
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and ACE2 cell surface is required for viral infection of cells. Mutations in RBD are present variants concern that have emerged independently worldwide. For example, B.1.1.7 lineage has a mutation (N501Y) its enhances to ACE2. There also alleles humans with mutations site. Here we perform detailed affinity kinetics analysis effect five common (K417N, K417T, N501Y, E484K, S477N) two (S19P K26R) on...
Chlorophylls are a fundamental class of tetrapyrroles and function as the central reaction center, accessory photoprotective pigments in photosynthesis. Their unique individual photochemical properties consequence tetrapyrrole macrocycle, structural chemistry coordination behavior phytochlorin system, specific substituent pattern. They achieve their full potential solar energy conversion by working concert highly complex, supramolecular structures such centers light-harvesting complexes...
Tetrapyrrole-containing proteins are one of the most fundamental classes enzymes in nature and it remains an open question to give a chemical rationale for multitude biological reactions that can be catalyzed by these pigment-protein complexes. There many processes where same (i.e., chemically identical) porphyrin cofactor is involved quite distinct reactions. For example, heme active oxygen transport storage (hemoglobin, myoglobin) incorporation molecular organic substrates (cytochrome...
Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported.We studied new case of SAM known to no DSG1 detail clinical, histopathologic, immunofluorescent, ultrastructural phenotype identify underlying molecular mechanisms this rare genodermatosis.Histopathologic, electron microscopy, immunofluorescent studies were performed. Whole-exome sequencing data...
Abstract The Protein Data Bank in Europe-Knowledge Base (PDBe-KB, https://pdbe-kb.org) is a community-driven, collaborative resource for literature-derived, manually curated and computationally predicted structural functional annotations of macromolecular structure data, contained the (PDB). goal PDBe-KB two-fold: (i) to increase visibility reduce fragmentation contributed by specialist data resources, make these more findable, accessible, interoperable reusable (FAIR) (ii) place their...
SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but role humans unknown. Here, we show that expressed somatic cells early developing gonad human influences sex determination. We identified two individuals with 46, XY disorders/differences development (DSD) chromosomal rearrangements encompassing locus a third individual DSD missense mutation SOX8. In vitro functional assays indicate this...
Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), function which still unknown. Our objective this study was to better define specific features POIKTMP through larger series patients. Clinical molecular data two families eight...
Abstract Fragment screening is used to identify binding sites and leads in drug discovery, but it often unclear which are functionally important. Here, data from 37 experiments, 1309 protein structures 1601 ligands were analysed. A method group by introduced clustered according profiles of relative solvent accessibility. This identified 293 unique ligand sites, grouped into four clusters (C1-4). C1 includes larger, buried, conserved, population missense-depleted enriched known functional...
The Dundee Resource for Sequence Analysis and Structure Prediction (DRSASP; http://www.compbio.dundee.ac.uk/drsasp.html) is a collection of web services provided by the Barton Group at University Dundee. DRSASP's flagship are JPred4 webserver secondary structure solvent accessibility prediction JABAWS 2.2 multiple sequence alignment, disorder prediction, amino acid conservation calculations, specificity-determining site prediction. DRSASP resources available through conventional interfaces...
SARS-CoV-2 Spike (Spike) binds to human angiotensin-converting enzyme 2 (ACE2) and the strength of this interaction could influence parameters relating virulence. To explore whether population variants in ACE2 binding hence infection, we selected 10 based on affinity predictions prevalence gnomAD measured their affinities kinetics for receptor domain through surface plasmon resonance (SPR) at 37°C. We discovered that reduce enhance binding, including three strongly inhibited (p.Glu37Lys, ΔΔG...
Abstract Protein evolution is constrained by structure and function, creating patterns in residue conservation that are routinely exploited to predict other features. Similar constraints should affect variation across individuals, but it only with the growth of human population sequencing this has been tested at scale. Now, constraint established applications pathogenicity prediction, not yet explored for structural inference. Here, we map 2.4 million variants 5885 protein families quantify...
A facile, experimentally calibrated computational procedure is described that affords the relative ordering of heme cofactor reduction potentials with respect to intrinsic shifts brought about by apoprotein induced heme-macrocycle distortion. The method utilizes heme-Fe partial atomic charges and useful computationally inexpensive B3LYP/3-21g calculated for simplified models extracted from Protein Data Bank incorporating only effects varying macrocycle conformations thereby delineating their...
Human genome sequencing has generated population variant datasets containing millions of variants from hundreds thousands individuals 1-3 . The show the genomic distribution genetic variation to be influenced on genic and sub-genic scales by gene essentiality, 1,4,5 protein domain architecture 6 presence features such as splice donor/acceptor sites. 2 However, data are still too sparse provide a comparative picture between individual residues in proteome. 1,6 Here, we overcome this sparsity...
Abstract SARS-CoV-2 invades host cells via an endocytic pathway that begins with the interaction of Spike glycoprotein (S-protein) and human Angiotensin-converting enzyme 2 (ACE2). Genetic variability in ACE2 may be one factor mediates broad-spectrum severity infection COVID-19 outcomes. We investigated capacity variation to influence a focus on predicting effect missense variants S-protein interaction. validated mCSM-PPI2 variant prediction algorithm 26 published mutant SARS-CoV binding...
Chemically identical tetrapyrrole cofactors such as hemes and chlorophylls participate in functionally diverse biological roles. An analysis of the available protein structural data for bacteriochlorophylls photosynthetic reaction center gives statistically reliable evidence hypothesis that induced cofactor conformation is a modulator bio-molecular function each center. The results serve general model to illustrate conformational control other proteins.
Ankyrin protein repeats bind to a wide range of substrates and are one the most common motifs in nature. Here, we collate high-quality alignment 7,407 ankyrin examine for first time, distribution human population variants from large-scale sequencing healthy individuals across this family. Population not randomly distributed genome but constrained by gene essentiality function. Accordingly, interpret context with evolutionary constraint structural features including secondary structure,...
Tetratricopeptide repeat (TPR) proteins belong to the class of α-solenoid proteins, in which repetitive units α-helical hairpin motifs stack form superhelical, often highly flexible structures. TPR domains occur a wide variety and perform key functional roles including protein folding, trafficking, cell cycle control post-translational modification. Here, we look at domain enzyme O-linked GlcNAc-transferase (OGT), catalyses O–GlcNAcylation broad range substrate proteins. A number...
Abstract The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and ACE2 cell surface is required for viral infection of cells. Mutations in RBD are present variants concern that have emerged independently worldwide. For example, more transmissible B.1.1.7 lineage has a mutation (N501Y) its enhances to ACE2. There also alleles humans with mutations site. Here we perform detailed affinity kinetics analysis effect five common (K417N, K417T, N501Y, E484K S477N)...
While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need new drugs with eradication now realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, causative agent HAT. Using phenotypic screening to guide structure–activity relationships, potent drug-like inhibitors were developed. Proof concept was established in an animal model hemolymphatic stage To...
Abstract The molecular evolution of a protein is constrained by its structure and function. This how patterns evolutionary conservation in multiple sequence alignment can be exploited algorithms like AlphaFold to predict other features. Human population sequencing offers the potential show similar trends within single species. However, although gene-level domain-level aggregation variants routinely applied, data still preclude simple residue-level analysis per protein. Here, we aggregate...
Abstract SARS-CoV-2 infection begins with the interaction of Spike (Spike) and human angiotensin-converting enzyme 2 (ACE2). To explore whether population variants in ACE2 might influence binding hence infection, we selected 10 based on affinity predictions prevalence gnomAD measured their affinities for receptor domain through surface plasmon resonance (SPR). We discovered that enhance reduce binding, including two distinct distributions enhanced Spike. p.Ser19Pro (ΔΔG = ± 0.59 0.08 kcal...
New and improved drugs are required for the treatment ultimate eradication of malaria. The efficacy front-line therapies is now threatened by emerging drug resistance; thus, new tools to support development with a lower propensity resistance needed. Here, we describe RESistance Mapping And Profiling (ResMAP) platform identification resistance-conferring mutations in