A5005998309- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Photosynthetic Processes and Mechanisms
- RNA modifications and cancer
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
- Fetal and Pediatric Neurological Disorders
- Viral Infectious Diseases and Gene Expression in Insects
- Advanced biosensing and bioanalysis techniques
- Porphyrin and Phthalocyanine Chemistry
- Photoreceptor and optogenetics research
- Cellular Mechanics and Interactions
- Algal biology and biofuel production
- Mitochondrial Function and Pathology
- Animal Virus Infections Studies
- Microbial Community Ecology and Physiology
- Vestibular and auditory disorders
- Advanced Electron Microscopy Techniques and Applications
- Cardiomyopathy and Myosin Studies
- Retinopathy of Prematurity Studies
- Molecular spectroscopy and chirality
University of Bristol
2020-2025
University of Groningen
2013-2016
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms that drive high infectivity, broad tissue tropism, and pathology. Our 2.85-angstrom cryo-electron microscopy structure of spike (S) glycoprotein reveals receptor binding domains tightly bind essential free fatty acid linoleic (LA) in three composite pockets. A similar pocket also appears...
The Commander complex is required for endosomal recycling of diverse transmembrane cargos and mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed VPS35L, VPS26C, VPS29; the CCC which contains twelve subunits: COMMD1-COMMD10 coiled-coil domain-containing (CCDC) proteins CCDC22 CCDC93. Combining X-ray crystallography, electron cryomicroscopy, silico predictions, we have assembled a complete structural model Commander. distantly related to Retromer but has...
LHCII is the most abundant membrane protein on earth. It participates in first steps of photosynthesis by harvesting sunlight and transferring excitation energy to core complex. Here we have analyzed complex green alga Chlamydomonas reinhardtii its association with Photosystem II (PSII) form multiprotein complexes. Several PSII supercomplexes different antenna sizes been purified, largest which contains three trimers (named S, M N) per monomeric core. A projection map at a 13Å resolution was...
As coronavirus disease 2019 (COVID-19) persists, severe acute respiratory syndrome 2 (SARS-CoV-2) variants of concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor binding domain (RBD) comprises a free fatty acid (FFA)–binding pocket. FFA stabilizes locked conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2, and VOCs bind essential...
Abstract As the global burden of SARS-CoV-2 infections escalates, so does evolution viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, RNA viruses can also display genetic diversity within single infected hosts co-existing evolving differently in distinct cell types. The BriSΔ variant, originally identified as a subpopulation from isolate hCoV-19/England/02/2020, comprises spike an eight amino-acid deletion encompassing furin recognition...
Despite continuing progress in kinesin enzyme mechanochemistry and emerging understanding of the cargo recognition machinery, it is not known how these functions are coupled controlled by α-helical coiled coils encoded a large component protein sequences. Here, we combine computational structure prediction with single-particle negative-stain electron microscopy to reveal coiled-coil architecture heterotetrameric kinesin-1 its compact state. An unusual flexion scaffold enables folding...
CRISPR-based DNA editing technologies enable rapid and accessible genome engineering of eukaryotic cells. However, the delivery genetically encoded CRISPR components remains challenging sustained Cas9 expression correlates with higher off-target activities, which can be reduced via Cas9-protein delivery. Here we demonstrate that baculovirus, alongside its cargo, used to package deliver proteins human Using protein-loaded baculovirus (pBV), or base editors proteins, leading efficient in By...
The electron-conducting circuitry of life represents an as-yet untapped resource exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure a de novo diheme "maquette" protein, 4D2, which subsequently use to create expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, then utilized experimental validation continuum electrostatic redox potential calculations. This demonstrates how...
Kinesin-1 is a dynamic heterotetrameric assembly of two heavy and light chains (KHC KLC) that mediates microtubule-based intracellular transport many different cargoes. The complex adopts compact, autoinhibited state activated by cargo-adaptor proteins containing specific short linear peptide motifs (SLiMs). These interact with the tetratricopeptide repeat (TPR) domains KLCs. mechanism coupling SLiM recognition to activation-associated conformational changes in unknown. Here we combine...
Nonsense-mediated mRNA decay (NMD) is an surveillance pathway involved in translational control and gene expression regulation. Core NMD factors UPF1, UPF2 UPF3B are conserved from yeast to humans essential target mRNAs with a premature stop codon for decay. binding UPF1 activates UPF1’s ATPase helicase activities, important its association the exon-junction complex efficient NMD. However, UPF2’s RNA remains largely uncharacterized. Here, we analyze nucleic acid binding, identifying first...
Summary Photosystem I (PSI) is a pigment protein complex catalyzing the light‐driven electron transport from plastocyanin to ferredoxin in oxygenic photosynthetic organisms. Several PSI subunits are highly conserved cyanobacteria, algae and plants, whereas others distributed differentially various Here we characterized structural functional properties of purified heterokont alga Nannochloropsis gaditana , showing that it organized as supercomplex including core an outer antenna, plants other...
Adenovirus-derived nanoparticles (ADDomer) comprise 60 copies of adenovirus penton base protein (PBP). ADDomer is thermostable, rendering the storage, transport, and deployment ADDomer-based therapeutics independent a cold chain. To expand scope ADDomers for new applications, we engineered ADDobodies, representing PBP crown domain, genetically separated from multimerization domain. We inserted heterologous sequences into hyper-variable loops, resulting in monomeric, thermostable ADDobodies...
Deciphering translation is of paramount importance for the understanding many diseases, and antibiotics played a pivotal role in this endeavour. Blasticidin S (BlaS) targets by binding to peptidyl transferase center large ribosomal subunit. Using biochemical, structural cellular approaches, we show here that BlaS inhibits both elongation termination Mammalia. Bound mammalian terminating ribosomes, distorts 3'CCA tail P-site tRNA larger extent than previously reported bacterial thus delaying...
Abstract COVID-19, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms driving high infectivity, broad tissue tropism and pathology. Our cryo-EM structure of spike (S) glycoprotein reveals that receptor binding domains (RBDs) tightly specifically bind essential free fatty acid (FFA) linoleic (LA) in three composite pockets. The pocket also appears be present highly...
Abstract The de novo design of simplified porphyrin-binding helical bundles is a versatile approach for the construction valuable biomolecular tools to both understand and enhance protein functions such as electron transfer, oxygen binding catalysis. However, methods utilised proteins by packing hydrophobic side chains into buried pocket ligands heme have typically created highly flexible, molten globule-like structures, which are not amenable structural determination, hindering precise...
Abstract Background Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches accelerate development of reagents against infectious pathogens. Methods Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection vivo immunization design, produce validate nature-inspired nanoparticle-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results Our resulted two...
Abstract COVID-19 continues to damage populations, communities and economies worldwide. Vaccines have reduced COVID-19-related hospitalisations deaths, primarily in developed countries. Persisting infection rates, highly transmissible SARS-CoV-2 Variants of Concern (VOCs) causing repeat breakthrough infections, underscore the ongoing need for new treatments achieve a global solution. Based on ADDomer, self-assembling protein nanoparticle scaffold, we created ADDoCoV, thermostable candidate...
Summary Adenovirus-derived dodecamer (ADDomer) nanoparticles comprise 60 copies of Adenovirus penton base protein (PBP). ADDomer is thermostable, rendering the storage, transport and deployment ADDomer-based therapeutics independent a cold-chain. To expand scope for new applications, we engineered ADDobodies. ADDobodies represent crown domain PBP, genetically separated from its multimerization domain. We inserted heterologous sequences into hyper-variable loops in The resulting were...
Nonsense-mediated mRNA decay (NMD) is an surveillance pathway involved in translational control and gene expression regulation. Core NMD factors UPF1, UPF2 UPF3B are conserved from yeast to humans essential target mRNAs with a premature stop codon for decay. binding UPF1 activates UPF1's ATPase helicase activities, important its association the exon-junction complex efficient NMD. However, UPF2's RNA remains largely uncharacterized. Here, we analyze nucleic acid binding, identifying first...
Abstract As the global burden of SARS-CoV-2 infections escalates, so does evolution viral variants which is particular concern due to their potential for increased transmissibility and pathology. In addition this entrenched variant diversity in circulation, RNA viruses can also display genetic within single infected hosts with co-existing evolving differently distinct cell types. The BriSΔ variant, originally identified as a subpopulation by passaging isolate hCoV-19/England/02/2020,...
Abstract As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes locked conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind...
Abstract Despite continuing progress in kinesin enzyme mechanochemistry and emerging understanding of the cargo recognition machinery, it is not known how these functions are coupled controlled by alpha-helical coiled coils encoded a large component protein sequences. Here, we combine computational structure prediction with single-particle negative stain electron microscopy to reveal coiled-coil architecture heterotetrameric kinesin-1, its compact state. An unusual flexion scaffold enables...