A5062177977- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- Enzyme Structure and Function
- RNA regulation and disease
- Genomics and Phylogenetic Studies
- Bacteriophages and microbial interactions
- Cancer-related molecular mechanisms research
- Biotin and Related Studies
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
- SARS-CoV-2 and COVID-19 Research
- Amino Acid Enzymes and Metabolism
- Pharmacovigilance and Adverse Drug Reactions
- Receptor Mechanisms and Signaling
- Cancer-related gene regulation
- Liver Disease Diagnosis and Treatment
- Hepatitis C virus research
- Mast cells and histamine
- Viral gastroenteritis research and epidemiology
- PI3K/AKT/mTOR signaling in cancer
- PARP inhibition in cancer therapy
- Pharmaceutical Practices and Patient Outcomes
- ATP Synthase and ATPases Research
- Stoma care and complications
Indian Institute of Science Bangalore
2018-2025
Combined Military Hospital
2022
National University of Medical Sciences
2022
Hamad Medical Corporation
2020-2021
Weill Cornell Medical College in Qatar
2020-2021
Hamad General Hospital
2020
CMH Lahore Medical College and Institute of Dentistry
2020
MRC Laboratory of Molecular Biology
2013-2016
Council of Scientific and Industrial Research
2010-2015
Centre for Cellular and Molecular Biology
2006-2015
Mitochondria have specialized ribosomes that diverged from their bacterial and cytoplasmic counterparts. We solved the structure of yeast mitoribosomal large subunit using single-particle cryo-electron microscopy. The resolution 3.2 angstroms enabled a nearly complete atomic model to be built de novo refined, including 39 proteins, 13 which are unique mitochondria, as well expansion segments RNA. reveals new exit tunnel path architecture, elements E site, putative membrane docking site.
Highlights•Structure of a partial yeast 48S translation initiation complex at 4.0 Å resolution•A distorted initiator tRNA is trapped in the act recognizing start codon•The codon-anticodon duplex stabilized by N-terminal tail eIF1A•eIF2α makes contacts with key nucleotides −2 and −3 positions mRNASummaryDuring eukaryotic initiation, does not insert fully into P decoding site on 40S ribosomal subunit. This conformation (POUT) compatible scanning mRNA for AUG codon. Base pairing thought to...
In bacterial translational initiation, three initiation factors (IFs 1–3) enable the selection of initiator tRNA and start codon in P site 30S ribosomal subunit. Here, we report 11 single-particle cryo-electron microscopy (cryoEM) reconstructions complex subunit with tRNA, mRNA, IFs 1–3, representing different steps along pathway. IF1 provides key anchoring points for IF2 IF3, thereby enhancing their activities. positions a domain an extended conformation appropriate capturing...
The last step in eukaryotic translational initiation involves the joining of large and small subunits ribosome, with initiator transfer RNA (Met-tRNA(i)(Met)) positioned over start codon messenger P site. This is catalyzed by factor eIF5B. We used recent advances cryo-electron microscopy (cryo-EM) to determine a structure eIF5B complex 6.6 angstrom resolution from <3% population, comprising just 5143 particles. reveals conformational changes eIF5B, tRNA, ribosome that provide insights into...
In eukaryotic translation initiation, AUG recognition of the mRNA requires accommodation Met-tRNAi in a 'PIN' state, which is antagonized by factor eIF1. eIF5 GTPase activating protein (GAP) eIF2 that additionally promotes stringent selection, but molecular basis its dual function was unknown. We present cryo-electron microscopy (cryo-EM) reconstruction yeast 48S pre-initiation complex (PIC), at an overall resolution 3.0 Å, featuring N-terminal domain (NTD) bound to 40S subunit location...
The SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. of Nsp1 (Nsp1-C-ter) from bind in the mRNA entry channel 40S ribosomal subunit blocks entry, thereby shutting down host synthesis. suppresses immune function is vital for viral replication. Hence, appears to be attractive target therapeutics. In this study, we have silico screened Food Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among top...
Editing/proofreading by aminoacyl-tRNA synthetases is an important quality control step in the accurate translation of genetic code that removes noncognate amino acids attached to tRNA. Defects process editing result disease conditions including neurodegeneration. While proofreading, cognate larger a methyl group are generally thought be sterically rejected modules as envisaged "Double-Sieve Model." Strikingly using solution based direct binding studies, NMR-heteronuclear single quantum...
The biological macromolecular world is homochiral and effective enforcement perpetuation of this homochirality essential for cell survival. In study, we present the mechanistic basis a configuration-specific enzyme that selectively removes D-amino acids erroneously coupled to tRNAs. crystal structure dimeric D-aminoacyl-tRNA deacylase (DTD) from Plasmodium falciparum in complex with substrate-mimicking analog shows how it uses an invariant ‘cross-subunit’ Gly-cisPro dipeptide capture chiral...
In Pakistan, substantial changes to hepatitis C virus (HCV) programming and treatment have occurred since the 2008 nationwide serosurvey estimated a 4.8% anti-HCV prevalence. absence of an updated national study, this analysis uses provincial data estimate prevalence interventions needed achieve elimination. Using Delphi process, epidemiologic HCV for four provinces Pakistan (accounting 97% population) were reviewed with 21 subject-matter experts in Pakistan. Province-level estimates...
Eukaryotic Initiation Factor 4 (eIF4) is a group of factors that activates mRNA for translation and recruit 43S preinitiation complex (PIC) to the 5′ end, forming 48S PIC. The eIF4 include cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A, scaffold eIF4G, which anchors eIF4A eIF4E. Another factor, eIF4B, stimulates activity facilitates recruitment. However, mechanisms by eIF4B binds 40S ribosomal subunit promotes recruitment remain poorly understood. Using cryo-Eletron Microscopy...
Abstract The eukaryotic initiation factor 3 (eIF3) complex is involved in every step of translation initiation, but there limited understanding its molecular functions. Here, we present a single particle electron cryomicroscopy (cryo-EM) reconstruction yeast 48S ribosomal preinitiation (PIC) an open conformation conducive to scanning, with core subunit eIF3b bound on the 40S interface near decoding center contact ternary eIF2·GTP·initiator tRNA. relocated together eIF3i from their solvent...
Abstract Proofreading modules of aminoacyl-tRNA synthetases are responsible for enforcing a high fidelity during translation the genetic code. They use strategically positioned side chains specifically targeting incorrect aminoacyl-tRNAs. Here, we show that unique proofreading module possessing D -aminoacyl-tRNA deacylase fold does not imparting specificity or catalysis, two hallmark activities enzymes. We show, using three distinct archaea, side-chain-stripped recognition site is fully...
The effect of polychlorinated biphenyls (PCB) on the state antioxidant system and lipid peroxidation in liver muscles two Black Sea fish species-Mullus barbatus Scorpaena porcus-has been studied. It was found that PCB were accumulated lesser amounts than liver. In activity enzymes did not differ significantly fishes kept sea water, aquarium or plus PCB, whereas there an increase lipoxygenase a decrease peroxidase activity. levels antioxidants (glutathione, carotenoids, vitamins A, E K)...
It is generally believed that human mature erythrocytes do not possess functional ribosomes and therefore cannot synthesize proteins. However, the absence of translation consistent with long lifespan erythrocytes. They stay viable for about 115 d in circulatory system. Here, using a highly pure preparation erythrocytes, we demonstrate presence by polysome profiling, [35S]methionine labeling, RiboPuromycylation. labeling revealed 10% observed reticulocytes. We could observe polysomes...
Regulation of mRNA translation plays a key role in the control gene expression. Scd6, conserved RGG-motif containing protein represses by binding to initiation factor eIF4G1. Here we report that Scd6 binds itself dependent manner and self-association regulates its repression activity. self-interaction competes with eIF4G1 methylation Hmt1 negatively affects self-association. Results pertaining Sbp1 indicate could be general feature repressor proteins. Taken together, our study reveals...
Abstract Background Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so elderly cohort of patients. Despite this, concept its prevention through prospective analysis has largely remained unexamined. We evaluated utility recently validated adverse drug reactions (ADR) avoidability tool a patients with DILI. Methods examined 38 DILI-drug pairs from n=38 presenting to Weill Cornell-affiliated tertiary hospital between February 2019 and...
Abstract mRNA translation is a fundamental process for life. Selection of the initiation site (TIS) crucial, as it establishes correct open reading frame decoding. Studies in vertebrate mRNAs discovered that purine at −3 and G +4 (where A AUG initiator codon numbered + 1), promote TIS recognition. However, context other eukaryotes has been poorly experimentally analyzed. We analyzed vitro influence −3, −2, −1 4 positions rabbit, Drosophila, wheat, yeast. observed −3A conferred best...
Accurate and high-speed scanning subsequent selection of the correct start codon are important events in protein synthesis. Eukaryotic mRNAs have long 5' UTRs that inspected for presence a by ribosomal 48S pre-initiation complex (PIC). However, conformational state PIC required inspecting every is not clearly understood. Here, atomistic molecular dynamics (MD) simulations energy calculations suggest conformation may reject all but 4 (GUG, CUG, UUG ACG) 63 non-AUG codons, initiation factor...