A5043013940- RNA and protein synthesis mechanisms
- Bacterial Genetics and Biotechnology
- Tuberculosis Research and Epidemiology
- Bacteriophages and microbial interactions
- Mycobacterium research and diagnosis
- SARS-CoV-2 and COVID-19 Research
- Viral gastroenteritis research and epidemiology
- RNA modifications and cancer
- Antibiotic Resistance in Bacteria
- Enzyme Structure and Function
- DNA Repair Mechanisms
- Neuropeptides and Animal Physiology
- Viral Infections and Immunology Research
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- PARP inhibition in cancer therapy
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- interferon and immune responses
- Pain Mechanisms and Treatments
- DNA and Nucleic Acid Chemistry
- Advanced Electron Microscopy Techniques and Applications
- Cancer therapeutics and mechanisms
- Cholesterol and Lipid Metabolism
- Photosynthetic Processes and Mechanisms
Rockefeller University
2016-2025
University of Alabama at Birmingham
1996-2024
The Wallace H. Coulter Department of Biomedical Engineering
2019-2021
Georgia Institute of Technology
2019-2021
Beam Therapeutics (United States)
2021
University of Wisconsin–Whitewater
2014
Columbia University
2012
NIHR Nottingham Digestive Diseases Biomedical Research Unit
2010
Washburn University
2007
University of Michigan
2006
The crystal structure of Thermus aquaticus RNA polymerase holoenzyme (α 2 ββ′ωσ A ) complexed with a fork-junction promoter DNA fragment has been determined by fitting high-resolution x-ray structures individual components into 6.5-angstrom resolution map. lies across one face the holoenzyme, completely outside active site channel. All sequence-specific contacts core elements are mediated σ subunit. universally conserved tryptophan is ideally positioned to stack on exposed base pair at...
Backtracking, the reverse motion of transcriptase enzyme on nucleic acid template, is a universal regulatory feature transcription in cellular organisms but its role viruses not established. Here we present evidence that backtracking extends into viral realm, where by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) may aid and replication. Structures SARS-CoV-2 RdRp bound to essential nsp13 helicase suggested facilitates backtracking. We use...
There has been recent evidence linking bradykinin (BK) receptors with inflammation. This study investigated the involvement of BK in two models persistent inflammatory hyperalgesia rats. In a Freund's adjuvant-induced model and an ultraviolet (UV)-induced rats specific B2 antagonist, D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-BK (HOE 140), was either ineffective or weakly active reversing hyperalgesia. The B1 des-Arg9, [Leu8]-BK, effective preventing development both UV-induced agonist, des-Arg9-BK,...
Bacterial DNA-dependent RNA polymerase (RNAP) has subunit composition β′βα I α II ω. The role of ω been unclear. We show that is homologous in sequence and structure to RPB6, an essential shared eukaryotic RNAP I, II, III. In Escherichia coli , overproduction suppresses the assembly defect caused by substitution residue 1362 largest RNAP, β′. yeast, RPB6 equivalent RPB1. High-resolution structural analysis ω–β′ interface bacterial comparison with RPB6–RPB1 yeast confirms relationship...
Summary Background Anxiety, depression and nongastrointestinal symptoms are often prominent in irritable bowel syndrome (IBS), but their relative value patient management has not been quantitatively assessed. We modified the Patient Health Questionnaire 15 (PHQ‐15) by excluding three gastrointestinal items to create PHQ‐12 Somatic Symptom (PHQ‐12 SS) scale. Aims To compare of SS scale with Hospital Anxiety Depression (HAD) predicting behaviour IBS diverticular disease. Methods compared 151...
Bacteriophage T7 encodes an essential inhibitor of the Escherichia coli host RNA polymerase (RNAP), product gene 2 (Gp2). We determined a series X-ray crystal structures E. RNAP holoenzyme with or without Gp2. The results define structure and location σ(70) subunit domain 1.1(σ(1.1)(70)) inside active site channel, where it must be displaced by DNA upon formation open promoter complex. associated data, combined previous results, allow for complete delineation mechanism Gp2 inhibition RNAP....
Coliphage HK022 Nun blocks superinfection by coliphage λ stalling RNA polymerase (RNAP) translocation specifically on DNA. To provide a structural framework to understand how RNAP translocation, we determined structures of Escherichia coli ternary elongation complexes (TECs) with and without single-particle cryo-electron microscopy. fits tightly into the TEC taking advantage gaps between nucleic acids. The C-terminal segment interacts β β’ subunits inside active site cleft as well nearly...
RbpA and CarD are essential transcription regulators in mycobacteria. Mechanistic analyses of promoter open complex (RPo) formation establish that cooperatively stimulate an intermediate (RP2) leading to RPo; RP2 is likely a bottleneck step at the majority mycobacterial promoters. Once RPo forms, also disfavors its isomerization back RP2. We determined 2.76 Å-resolution crystal structure initiation (TIC) with as well CarD/RbpA/TIC model. Both bind near upstream edge -10 element where they...
Fidaxomicin (Fdx) is an antimicrobial RNA polymerase (RNAP) inhibitor highly effective against Mycobacterium tuberculosis RNAP in vitro, but clinical use of Fdx limited to treating Clostridium difficile intestinal infections due poor absorption. To identify the structural determinants binding RNAP, we determined 3.4 Å cryo-electron microscopy structure a complete M. holoenzyme complex with Fdx. We find that actinobacteria general transcription factor RbpA contacts fidaxomycin, explaining its...
We report crystal structures of the antibacterial lasso peptides microcin J25 (MccJ25) and capistruin (Cap) bound to their natural enzymatic target, bacterial RNA polymerase (RNAP). Both bind within RNAP secondary channel, through which NTP substrates enter active site, sterically block trigger-loop folding, is essential for efficient catalysis by RNAP. MccJ25 binds deep channel in a manner expected interfere with substrate binding, explaining partial competitive mechanism inhibition respect...