A5057082623- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Bacterial Genetics and Biotechnology
- Veterinary medicine and infectious diseases
- Toxin Mechanisms and Immunotoxins
- Antimicrobial Resistance in Staphylococcus
- Bacteriophages and microbial interactions
- Genomics and Phylogenetic Studies
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Microbial Natural Products and Biosynthesis
- Chemical Synthesis and Analysis
- Origins and Evolution of Life
- Mycobacterium research and diagnosis
- RNA Research and Splicing
- Protein Structure and Dynamics
- Sarcoidosis and Beryllium Toxicity Research
- Infective Endocarditis Diagnosis and Management
- Advanced Electron Microscopy Techniques and Applications
- Tuberculosis Research and Epidemiology
- Biopolymer Synthesis and Applications
- Clostridium difficile and Clostridium perfringens research
- Biochemical and Molecular Research
- Parasitic Infections and Diagnostics
Weizmann Institute of Science
2015-2025
Google (United States)
2011
University of Padua
2005
Max Planck Institute for Molecular Genetics
1999
Although the mode of action ribosomes, multi-component universal effective protein-synthesis organelles, has been thoroughly explored, their mere appearance remained elusive. Our earlier comparative structural studies suggested that a internal small RNA pocket-like segment called by us protoribosome, which is still embedded in contemporary ribosome, vestige primordial ribosome. Herein, after constructing such pockets, we show using "fragment reaction" and its analyses MALDI-TOF LC-MS mass...
New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to ribosome. The crystal structures Deinococcus radiodurans large ribosomal subunit complexed with each three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, SB-571519, show that all bind PTC their core oriented similarly A-site C14 extensions pointing toward P-site. Except for an H-bond network a single nucleotide, G2061,...
The emergence of bacterial multidrug resistance to antibiotics threatens cause regression the preantibiotic era. Here we present crystal structure large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with known linezolid telithromycin, as well new, highly potent pleuromutilin derivative, BC-3205. These structures shed light on specific structural motifs S. aureus ribosome binding modes aforementioned antibiotics. Moreover, by...
The increasing appearance of pathogenic bacteria with antibiotic resistance is a global threat. Consequently, clinically available potent antibiotics that are active against multidrug resistant pathogens becoming exceedingly scarce. Ribosomes main target for antibiotics, and hence an objective novel drug development. Lefamulin, semi-synthetic pleuromutilin compound highly multi-resistant pathogens, promising currently in phase III trials the treatment community-acquired bacterial pneumonia...
Abstract Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to poor selection drugs that mostly target elements in the parasite’s cell envelope. Here we determined atomic resolution electron cryo-microscopy (cryo-EM) structure ribosome complex paromomycin (PAR), highly potent compound recently approved for treatment fatal visceral leishmaniasis (VL). The reveals mechanism by which drug induces its deleterious effects on...
Abstract Formation of 100S ribosome dimer is generally associated with translation suppression in bacteria. Trans -acting factors modulation factor (RMF) and hibernating promoting (HPF) were shown to directly mediate this process E. coli . Gram-positive S. aureus lacks an RMF homolog the structural basis for its formation was not known. Here we report cryo-electron microscopy structure native from , revealing molecular mechanism formation. The distinct previously reported analogs relies on...
Leishmania is a single-cell eukaryotic parasite of the Trypanosomatidae family, whose members cause an array tropical diseases. The often fatal outcome infections, lack effective vaccines, limited selection therapeutic drugs, and emerging resistant strains, underline need to develop strategies combat these pathogens. Trypanosomatid ribosome has recently been highlighted as promising target due structural features that are distinct from other eukaryotes. Here, we present 2.8-Å resolution...
Antimicrobial resistance within a wide range of pathogenic bacteria is an increasingly serious threat to global public health. Among these are the highly resistant, versatile and possibly aggressive bacteria, Staphylococcus aureus. Lincosamide antibiotics were proved be effective against this pathogen. This small, albeit important group mostly active Gram-positive but also used selected Gram-negative anaerobes protozoa. S. aureus lincosamides can acquired by modifications and/or mutations in...
The electron density map of the small ribosomal subunit from Thermus thermophilus , constructed at 4.5 Å resolution, shows recognizable morphology this particle, as well structural features that were interpreted RNA and proteins. Unbiased assignments, carried out by quantitative covalent binding heavy atom compounds predetermined sites, led to localization surface protein S13 a position compatible with previous whereas S11 was localized distance about twice its diameter site suggested for...
Trigger factor (TF), the first chaperone in eubacteria to encounter emerging nascent chain, binds large ribosomal subunit vicinity of protein exit tunnel opening and forms a sheltered folding space. Here, we present 3.5-Å crystal structure physiological complex from eubacterium Deinococcus radiodurans with N-terminal domain TF (TFa) same organism. For anchoring, TFa exploits small surface area proteins L23 L29, by using its “signature motif” as well additional structural elements. The...
Using quantum mechanics and exploiting known crystallographic coordinates of tRNA substrate located in the ribosome peptidyl transferase center around 2-fold axis, we have investigated mechanism for peptide-bond formation. The calculation is based on a choice 50 atoms assumed to be important mechanism. We used density functional theory optimize geometry energy transition state (TS) TS formed simultaneously with rotatory motion enabling translocation A-site 3' end into P site, estimated...
Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at peptidyl transferase center of eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding showed interference with peptide bond formation. Chemical probing indicated macrolide lankamycin, a second same species, neighboring site, ribosome exit tunnel. These two antibiotics can bind to simultaneously display synergy in inhibiting...
Abstract The clinical use of the antibiotic erythromycin (ery) is hampered owing to spread resistance genes that are mostly mutating rRNA around ery binding site at entrance protein exit tunnel. Additional effective mechanisms include deletion or insertion mutations in ribosomal uL22, which lead alterations tunnel shape, located 16 Å away from drug’s site. We determined cryo-EM structures Staphylococcus aureus 70S ribosome, and its bound complex with a two amino acid mutation ß hairpin loop,...
The structures of the large ribosomal subunit Deinococcus radiodurans (D50S) in complex with antibiotic lankamycin (3.2 Å) and a double lankacidin C (3.45 have been determined, continuation previous crystallographic studies on lankacidin-D50S complex. These two drugs previously reported to inhibit function mild synergistic effect. Lankamycin, member macrolide family, binds similar manner erythromycin. However, when lankacidin, is located so that it can form interactions adjacent binding...
Based on the presumed capability of a prebiotic pocket-like entity to accommodate substrates whose stereochemistry enables creation chemical bonds, it is suggested that universal symmetrical region identified within all contemporary ribosomes originated from an we term 'proto-ribosome'. This 'proto-ribosome' could have evolved earlier machine was capable performing essential tasks in RNA world, called here 'pre-proto-ribosome', which adapted for producing proteins.