A5064504122- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- Animal Virus Infections Studies
- RNA modifications and cancer
- DNA Repair Mechanisms
- Viral gastroenteritis research and epidemiology
- Advanced Electron Microscopy Techniques and Applications
- Cytomegalovirus and herpesvirus research
- DNA and Nucleic Acid Chemistry
- Enzyme Structure and Function
- Scientific Computing and Data Management
- Metabolomics and Mass Spectrometry Studies
- Respiratory viral infections research
- Parvovirus B19 Infection Studies
- Microtubule and mitosis dynamics
- RNA Research and Splicing
- RNA Interference and Gene Delivery
- Genomics and Phylogenetic Studies
- Bacteriophages and microbial interactions
- Plant Virus Research Studies
- Molecular Biology Techniques and Applications
- Health, Environment, Cognitive Aging
- Genetics, Bioinformatics, and Biomedical Research
- Advanced biosensing and bioanalysis techniques
- Electron and X-Ray Spectroscopy Techniques
MRC Laboratory of Molecular Biology
2019-2024
The University of Melbourne
2023-2024
ARC Centre of Excellence in Advanced Molecular Imaging
2023
University of Helsinki
2012-2020
Czech Academy of Sciences, Institute of Biotechnology
2014
Jamia Millia Islamia
2006-2007
Assembly of the major viral pathogens Picornaviridae family is poorly understood. Human parechovirus 1 an example such viruses that contains 60 short regions ordered RNA density making identical contacts with protein shell. We show here via a combination RNA-based systematic evolution ligands by exponential enrichment, bioinformatics analysis and reverse genetics these segments are bound to coat proteins in sequence-specific manner. Disruption either recognition motif or its contact amino...
ABSTRACT Coxsackievirus A9 (CVA9) is an important pathogen of the Picornaviridae family. It utilizes cellular receptors from integrin α v family for binding to its host cells prior entry and genome release. Among integrins tested, it has highest affinity β 6 , which recognizes arginine-glycine-aspartic acid (RGD) loop present on C terminus viral capsid protein, VP1. As atomic model CVA9 lacks RGD loop, we used surface plasmon resonance, electron cryo-microscopy, image reconstruction...
ABSTRACT Coxsackievirus A7 (CAV7) is a rarely detected and poorly characterized serotype of the Enterovirus species Human enterovirus A ( HEV-A ) within Picornaviridae family. The CAV7-USSR strain has caused polio-like epidemics was originally thought to represent fourth poliovirus type, but later evidence linked this CAV7-Parker prototype. Another isolate, CAV7-275/58, also serologically similar Parker noninfectious in mouse model. Sequencing genomic region encoding capsid proteins USSR...
Abstract The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available. Our 4.3-Å resolution structure of HPeV3 on its own and at 15 Å in complex monoclonal antibody Fabs demonstrates the expected picornavirus capsid three distinct features. First, 25% RNA genome 60 sites is highly ordered as confirmed by asymmetric reconstruction, interacts conserved regions proteins VP1 VP3. Second, VP0 N terminus stabilizes inner surface, contrast to...
Embryonic regulators are often re-expressed in cancers, however the functional and molecular significance of this is not always understood. The epigenetic priming factors Developmental Pluripotency Associated 2 4 (DPPA2/4) have crucial roles early development implicated cancer pathogenesis. We reveal non-small cell lung (NSCLC), DPPA2/4 co-expression associated with poorly differentiated tumours, impaired patient outcomes accelerated vivo xenograft tumour growth. Proteomic analyses dimerise...
ABSTRACT Since it was first recognized in 2004 that human parechoviruses (HPeV) are a significant cause of central nervous system and neonatal sepsis, their clinical importance, primarily children, has started to emerge. Intravenous immunoglobulin treatment is the only available such life-threatening cases given moderate success. Direct inhibition parechovirus infection using monoclonal antibodies potential treatment. We have developed two neutralizing against HPeV1 HPeV2, namely, AM18 AM28,...
Plasmodium falciparum Pfs230 and Pfs48/45, part of a core fertilization complex, are leading malaria transmission-blocking vaccine candidates. However, how the two proteins interact is unknown. Here we report 3.36 Å resolution cryo-electron microscopy structure endogenous Pfs230-Pfs48/45 complex. We show that Pfs48/45 interacts with domains 13 14, not included in current immunogens. Using transgenic parasite line domain to 14 deletion, these essential for localization on gamete surface....
Fitting of atomic components into electron cryo-microscopy (cryoEM) density maps is routinely used to understand the structure and function macromolecular machines. Many fitting methods have been developed, but a standard protocol for successful assessment fitted models has yet be agreed upon among experts in field. Here, we created tested that highlights important issues related homology modelling, map segmentation, rigid flexible fitting, as well fits. As part it, use two different...
Human parechovirus 3 (HPeV3), a member of the Picornavirus family, is frequently detected worldwide. However, observed seropositivity rates for HPeV3 neutralizing antibodies (nAbs) vary from high in Japan to low Netherlands and Finland. To study if this can be explained by technical differences or antigenic diversity among strains included serological studies, we determined activity Japanese Dutch intravenous immunoglobulin batches (IVIG), rabbit hyperimmune polyclonal serum, human...
Cryo-electron microscopy of protein complexes often leads to moderate resolution maps (4–8 Å), with visible secondary-structure elements but poorly resolved loops, making model building challenging. In the absence high-resolution structures homologues, only coarse-grained structural features are typically inferred from these maps, and it is impossible assign specific regions density individual subunits. This paper describes a new method for overcoming difficulties that integrates predicted...
Abstract Human parechoviruses (HPeV) are picornaviruses with a highly-ordered RNA genome contained within icosahedrally-symmetric capsids. Ordered structures have recently been shown to interact capsid proteins VP1 and VP3 facilitate virus assembly in HPeV1. Using an assay that combines reversible cross-linking, affinity purification peptide mass fingerprinting (RCAP), we mapped the RNA-interacting regions of from whole HPeV1 virion solution. The intrinsically-disordered N-termini VP3,...
Abstract Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of frequently phosphorylated damage, promotes cancer progression, but its role remains unclear. Here, we report molecular characterisation full-length, demonstrating preference for binding open functioning as sliding clamp. We identified phosphate interacting motif within CTD that dictates ATP hydrolysis...
Abstract Proteins are comprised of structured domains and dynamic regions, both essential for biological function. However, studying regions is challenging using most structural biology methods, including crosslinking mass spectrometry. Here, we dramatically improve the usefulness distance restraints from MS by taking advantage short-lived reactive species generated diazirine-based photo-crosslinking. This leads to a clear view complex topologies conformational changes, in regions. We...
Abstract Nora virus, a virus of Drosophila , encapsidates one the largest single-stranded RNA genomes known. Its taxonomic affinity is uncertain as it has picornavirus-like cassette enzymes for replication, but capsid structure was at time genome publication unknown. By solving and through sequence comparison, we clear up this ambiguity in invertebrate virosphere. Despite lack detectable similarity amino acid sequences, 2.7 Å resolution cryoEM map showed to have T = 1 symmetry with...
Vertebrate DNA crosslink repair is a crucial process that excises toxic replication-blocking interstrand crosslinks 1 . This pathway fails in the inherited human disease Fanconi anemia (FA), resulting abnormal development, loss of blood production, and marked cancer susceptibility 2 Numerous factors involved have been identified, mutations their corresponding genes cause FA 3 A biochemical description how gene products might initiate removal now emerging. However, structural insight into...
Abstract Cryo-electron microscopy of protein complexes often leads to moderate resolution maps (4-8 Å), with visible secondary structure elements but poorly resolved loops, making model-building challenging. In the absence high-resolution structures homologues, only coarse-grained structural features are typically inferred from these maps, and it is impossible assign specific regions density individual subunits. This paper describes a new method for overcoming difficulties that integrates...