A5003634348- RNA modifications and cancer
- Cancer-related gene regulation
- RNA Research and Splicing
- Metal-Catalyzed Oxygenation Mechanisms
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Metal complexes synthesis and properties
- Crystal structures of chemical compounds
- Eicosanoids and Hypertension Pharmacology
- Computational Drug Discovery Methods
- S100 Proteins and Annexins
- Lanthanide and Transition Metal Complexes
- COVID-19 Clinical Research Studies
- Microbial metabolism and enzyme function
- Magnetism in coordination complexes
- Microbial Metabolism and Applications
- Hepatitis C virus research
- Cancer-related molecular mechanisms research
- SARS-CoV-2 and COVID-19 Research
- Chemical Thermodynamics and Molecular Structure
- Biochemical effects in animals
- Fuel Cells and Related Materials
- Porphyrin and Phthalocyanine Chemistry
Hong Kong Baptist University
2020-2024
Columbia University
2017-2023
ShanghaiTech University
2023
Kowloon Hospital
2020
University of Oxford
2012-2015
Oxford Research Group
2015
Mansfield University
2012
Abstract ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N6-methyladenine in RNA. upregulated under hypoxia plays role spermatogenesis. We describe crystal structure human (residues 66–292) to 2.0 Å resolution. ALKBH566–292 has double-stranded β-helix core fold as observed other 2OG family members. The active site metal octahedrally coordinated by an HXD…H motif (comprising residues His204, Asp206 His266) three...
N(6)-Methyladenosine (m(6)A) is the most prevalent internal RNA modification in eukaryotes. ALKBH5 belongs to AlkB family of dioxygenases and has been shown specifically demethylate m(6)A single-stranded RNA. Here we report crystal structures presence either its cofactors or inhibitor citrate. Catalytic assays demonstrate that catalytic domain can both DNA. We identify TCA cycle intermediate citrate as a modest ALKHB5 (IC50, ∼488 μm). The structural analysis reveals loop region immobilized...
2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) 4-carboxy-8-hydroxyquinoline (4C8HQ) with that two other commonly used inhibitors, N-oxalylglycine (NOG) 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal IOX1 has broad spectrum activity, as demonstrated by inhibition transcription factor hydroxylases, representatives all...
The fat mass and obesity associated protein (FTO) is a potential target for anti-obesity medicines. FTO 2-oxoglutarate (2OG)-dependent N-methyl nucleic acid demethylase that acts on substrates including 3-methylthymidine, 3-methyluracil, 6-methyladenine. To identify inhibitors, we screened set of 2OG analogues related compounds using differential scanning fluorometry- liquid chromatography-based assays. results revealed sets both cyclic acyclic are inhibitors. Identified inhibitors include...
Architecture of an mRNA processor The 3′-end processing the three major classes RNA polymerase II transcripts in metazoan cells—polyadenylated messenger RNAs (mRNAs), histone mRNAs, and small nuclear (snRNAs)—requires distinct machineries that share common features. Sun et al. reconstituted active human pre-mRNA machinery solved its structure at near-atomic resolution by cryo–electron microscopy. This provides a basis for understanding mechanism shared catalytic reactions between canonical...
The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), is a global threat to human health. Using multidisciplinary approach, we identified and validated hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load multiple orders magnitude synergizes with remdesivir in vitro. Mechanistically, showed that not only inhibits...
Abstract AlkB homologue 5 (ALKBH5) is a ferrous iron and 2-oxoglutarate dependent oxygenase that demethylates RNA N6-methyladenosine (m6A), post-transcriptional modification with an emerging set of regulatory roles. Along the fat mass obesity-associated protein (FTO), ALKBH5 one only two identified human m6A oxidizing enzymes potential target for cancer treatment. Unlike FTO, efficiently catalyzes fragmentation its proposed nascent hemiaminal intermediate to give formaldehyde demethylated...
Significance The Fe(II)- and 2-oxoglutarate (2OG)-dependent hypoxia-inducible transcription factor prolyl-hydroxylases play a central role in human oxygen sensing are related to other involved eukaryotic collagen biosynthesis ribosomal modification. finding that PHD-related prolyl-hydroxylase Pseudomonas spp. regulates pyocyanin supports prokaryotic origins for the prolyl-hydroxylases. identification of switch I loop elongation Tu (EF-Tu) as domain containing protein (PPHD) substrate...
2-Oxoglutarate-dependent nucleic acid demethylases are of biological interest because their roles in repair and modification. Although some these enzymes linked to physiology, regulatory unclear. Hence, there is a desire develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable inhibition by small molecules. Dynamic combinatorial chemistry mass spectrometric analyses (DCMS) led the identification lead compounds, one was analyzed crystallography....
In 2007, a genome wide association study identified SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for protective allele. is DNA/RNA demethylase, however, how this function affects weight, if at all, unknown. Here we aimed to pharmacologically inhibit examine effect its demethylase vitro and vivo as first step evaluating therapeutic potential FTO. We...
Unlike canonical pre-mRNAs, animal replication-dependent histone pre-mRNAs lack introns and are processed at the 3'-end by a mechanism distinct from cleavage polyadenylation. They have 3' stem loop downstream element (HDE) that recognized stem-loop binding protein (SLBP) U7 snRNP, respectively. The N-terminal domain (NTD) of Lsm11, component interacts with FLASH NTD these two proteins recruit complex containing CPSF-73 endonuclease for reaction. Here, we determined crystal structures found...
Abstract The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), is a global threat to human health. Using multidisciplinary approach, we identified and validated hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load multiple orders magnitude synergizes with remdesivir in vitro . Mechanistically, showed that...
Solid-phase fluorescent BODIPY–peptide synthesis <italic>via in situ</italic> dipyrrin construction offers an efficient peptide synthetic platform for multifaceted biomedical applications.
Metazoan replication-dependent histone pre-mRNAs are cleaved at the 3′ end by U7 snRNP, an RNA-guided endonuclease that contains snRNA, seven proteins of Sm ring, FLASH, and four polyadenylation factors: symplekin, CPSF73, CPSF100, CstF64. A fully recombinant snRNP was recently reconstituted from all 13 components for functional structural studies shown to accurately cleave pre-mRNAs. Here, we analyzed activity in more detail. We demonstrate addition cleaving endonucleolytically, acts as a...
FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including demethylation N6-methyladenosine (m6A) in mRNA. is a proposed target for anti-cancer therapy. Using information from crystal structures complex with 2OG substrate mimics, we designed synthesized two series inhibitors, which were characterized by turnover binding assays, X-ray crystallography related bacterial enzyme AlkB. A potent inhibitor employing interactions spanning sites was...
In animal cells, replication-dependent histone pre-mRNAs are cleaved at the 3' end by U7 snRNP consisting of two core components: a ∼60-nucleotide snRNA and ring seven proteins, with Lsm10 Lsm11 replacing spliceosomal SmD1 SmD2. interacts FLASH together they recruit endonuclease CPSF73 other polyadenylation factors, forming catalytically active holo snRNP. Here, we assembled bound to from recombinant components analyzed its appearance electron microscopy ability support pre-mRNA processing...
U7 snRNP is a multi-subunit endonuclease required for 3' end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, lacks Sm subunits D1 and D2 instead contains two related proteins, Lsm10 Lsm11. The remaining five heptameric ring, SmE, F, G, B D3, are shared with snRNPs. pathway that assembles unique ring unknown. Here, we show heterodimer Lsm11 tightly interacts methylosome, complex arginine methyltransferase PRMT5, MEP50 pICln known...
U7 snRNP is a multisubunit endonuclease required for 3′ end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, lacks Sm subunits D1 and D2 instead contains two related proteins, Lsm10 Lsm11. The remaining five heptameric ring, SmE, F, G, B, D3, are shared with snRNPs. pathway that assembles unique ring unknown. Here, we show heterodimer Lsm11 tightly interacts methylosome, complex arginine methyltransferase PRMT5, MEP50, pICln known...