Figure 8 - uploaded by Wai Keat Yam
Content may be subject to copyright.
Distance for selected H-bonds suggested by Schlünzen and co-workers (8) as seen in this 1.3 ns simulation. Majority H-bonds had its distance for >3.50 Å when approaching equilibration and production stages. As a result, H-bonds between them were no longer formed and this result did not show agreement with the pattern found in crystal structure.
Source publication
Macrolides are a group of diverse class of naturally occurring and synthetic antibiotics made of macrocyclic-lactone ring carrying one or more sugar moieties linked to various atoms of the lactone ring. These macrolides selectively bind to a single high affinity site on the prokaryotic 50S ribosomal subunit, making them highly effective towards a w...
Contexts in source publication
Context 1
... that were found in the crystal structure were H-bonds between 2ʹOH group of desosamine sugar with N1 and N6 of A2041 and to N6 of A2042, 6-OH group of lactone ring with N6@A2045, 11-OH group of lactone ring with O4@U2588 and 12-OH group of lactone ring with O4 at U2588. In our simulation, all of these H-bonds (except H-bond between O12 and O4@U2588) were found to have bonds length >3.50 Å in most of the simulation time and none of them were able to form permanent H-bonds ( Figure 8). The importance of the H-bonds between nucleotides A2041 (A2058EC) and A2042 (A2059EC) and mac- rolides were previously shown by crystallography studies (8,59,60). ...
Context 2
... only interaction that we were able to associate with A2041 and A2042 is the H-bond between 2ʹOH of desosamine sugar and N1@A2041 that was found in the very early stage of the simulation. However, as simulation time evolved, this H-bond slowly disappearing during the equilibration stage and it was totally distorted shortly after this stage ( Figure 8). ...
Similar publications
An understanding of the mechanisms underlying protein aggregation and cytotoxicity of the protein aggregates is crucial in the prevention of several diseases in humans. Ribosome, the cellular protein synthesis machine is capable of acting as a protein folding modulator. The peptidyltransferase center residing in the domain V of large ribosomal subu...
Modified nucleosides of ribosomal RNA are synthesized during ribosome assembly. In bacteria, each modification is made by a specialized enzyme. In vitro studies have shown that some enzymes need the presence of ribosomal proteins while other enzymes can modify only protein-free rRNA. We have analyzed the addition of modified nucleosides to rRNA dur...
Resistance to macrolides and ketolides occurs mainly via alterations in RNA moieties of the drug-binding site. Using an A2058G
mutant of Mycobacterium smegmatis, additional telithromycin resistance was acquired via deletion of 15 residues from protein L22. Molecular modeling, based
on the crystal structure of the large ribosomal subunit from Deinoc...
Intramolecular RNA cross-links were induced within the large ribosomal subunit of E. coli by mild ultraviolet irradiation. Regions of the 23S RNA previously implicated in interactions with ribosomal-bound tRNA were
then specifically excised by addressed cleavage using ribonuclease H, in conjunction with synthetic complementary decadeoxyribonucleoti...
We have investigated protein-rRNA cross-links formed in 30S and 50S ribosomal subunits of Escherichia coli and Bacillus stearothermophilus at the molecular level using UV and 2-iminothiolane as cross-linking agents. We identified amino acids cross-linked to rRNA for 13 ribosomal proteins from these organisms, namely derived from S3, S4, S7, S14, S1...
Citations
... The crystal structure showed that both macrolides interact exclusively with Domain V of the 23S rRNA, at the entrance of the peptide exit tunnel in the peptidyl transferase center, 7 while other experimental studies revealed that these macrolides also interact with the Helix 35 of Domain II. 6,[8][9][10][11][12] Besides that, our previous MD studies also demonstrated a possible interaction with the Domain IV. 13 These macrolides showed high drug affinity and specificity to the ribosome with K d in the nanomolar range as measured by equilibrium dialysis, 14 footprinting protection experiments, 6,9,15 and binding kinetics 16,17 studies. The actual inhibition mode of ERYA and ROX to the bioactivity of ribosome is so far understood to the most general idea only. ...
... MD simulations of a large ribosomal subunit complexed with ERYA and ROX systems were performed for 2.5 ns. Preliminary MD results on a large ribosomal subunit complexed with the ERYA system has been reported, 13 and a further energetic analysis on this system is reported here. The MM-PBSA method was used to calculate the binding free energies of both systems comprising ERYA and ROX with the binding pocket in the 50S ribosomal subunit. ...
... The initial three-dimensional structure of the 50S large ribosomal subunit complexed with ERYA (Protein Data Bank code: 1JZY 7 ), including 23S rRNA, three chains of ribosomal proteins L4, L22, and L32, and two crystallographic magnesium ions, was used as a starting point. Residues that were missing from this X-ray crystal structure were reconstructed as described in ref 13, and all hydrogen atoms were added explicitly using the LEAP module of the AMBER 8 package. 20 The Amber 99 (RNA) all atom force field 21 was applied to describe the molecular mechanics for the ribosomal subunit, while the general amber force field (GAFF) 22 was used to describe the inhibitors. ...
Erythromycin A and roxithromycin are clinically important macrolide antibiotics that selectively act on the bacterial 50S large ribosomal subunit to inhibit bacteria's protein elongation process by blocking the exit tunnel for the nascent peptide away from ribosome. The detailed molecular mechanism of macrolide binding is yet to be elucidated as it is currently known to the most general idea only. In this study, molecular dynamics (MD) simulation was employed to study their interaction at the molecular level, and the binding free energies for both systems were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The calculated binding free energies for both systems were slightly overestimated compared to the experimental values, but individual energy terms enabled better understanding in the binding for both systems. Decomposition of results into residue basis was able to show the contribution of each residue at the binding pocket toward the binding affinity of macrolides and hence identified several key interacting residues that were in agreement with previous experimental and computational data. Results also indicated the contributions from van der Waals are more important and significant than electrostatic contribution in the binding of macrolides to the binding pocket. The findings from this study are expected to contribute to the understanding of a detailed mechanism of action in a quantitative matter and thus assisting in the development of a safer macrolide antibiotic.
Six new 16-membered macrolides with a rare branched octose unit, aldgamycins J-O (1-6), along with two known compounds, swalpamycin B (7) and chalcomycin (8), were isolated from Streptomyces sp. HK-2006-1. Their structures were determined by detailed spectroscopic and X-ray crystallographic analysis. Natural products containing branched sugar units are rare. Aldgaropyranose and decarboxylated aldgaropyranose are branched octoses, specifically aldgarose-type branched octose. Until now, only 11 compounds have been reported to contain an aldgarose-type branched octose. The discovery of aldgamycins J-O (1-6) adds new members of this type of natural product. All the compounds (1-8) herein were tested for antimicrobial activities against Gram-positive Staphylococcus aureus 209P, Gram-negative Escherichia coli ATCC0111, and two fungi, Candida albicans FIM709 and Aspergillus niger R330. Most of these compounds showed antibacterial activity against S. aureus. Their preliminary structure-activity relationships are proposed.