A5076351503- Protein Degradation and Inhibitors
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Genomics, phytochemicals, and oxidative stress
- Genomics and Chromatin Dynamics
- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Histone Deacetylase Inhibitors Research
- Sirtuins and Resveratrol in Medicine
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Glutathione Transferases and Polymorphisms
- Mitochondrial Function and Pathology
- Computational Drug Discovery Methods
- Cancer-related gene regulation
- Coenzyme Q10 studies and effects
- Cholinesterase and Neurodegenerative Diseases
- Protein Structure and Dynamics
- Genetic Neurodegenerative Diseases
- RNA modifications and cancer
- Biochemical effects in animals
- Polyamine Metabolism and Applications
- SARS-CoV-2 and COVID-19 Research
- Chemical Synthesis and Analysis
National Institute of Mental Health and Neurosciences
2015-2024
National Institute of Mental Health
2020
Systems Biology Institute
2008-2013
Laurus labs (India)
2008-2010
Industrial Credit and Investment Corporation of India
2008-2010
RIKEN Center for Integrative Medical Sciences
2004-2008
Goethe University Frankfurt
2008
GTx (United States)
2008
Japan Science and Technology Agency
2000-2005
All India Institute of Medical Sciences
1992-1996
Nrf2 is the regulator of oxidative/electrophilic stress response. Its turnover maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form hinge and latch. The E3 ligase adaptor Keap1 recognizes through its conserved ETGE DLG motifs. In this study, we examined how motifs bind to very similar fashion but with different affinities comparing crystal complex Keap1-DC domain-DLG peptide that domain-ETGE peptide. We...
Recognition of acetylated chromatin by the bromodomains and extra-terminal domain (BET) family proteins is a hallmark for transcriptional activation anchoring viral genomes to mitotic chromosomes host. One BET BRD2 interacts with during mitosis leads in culture cells. Here, we report crystal structures N-terminal bromodomain human (BRD2-BD1; residues 74-194) complex each three different Lys-12-acetylated H4 peptides. The BRD2-BD1 recognizes tail at Lys-12 (H4K12ac), whereas side chain...
The BET (bromodomains and extra terminal domain) family proteins recognize acetylated chromatin through their bromodomain act as transcriptional activators. One of the proteins, BRD2, associates with transcription factor E2F, mediator components CDK8 TRAP220, RNA polymerase II, well during mitosis. BRD2 contains two bromodomains (BD1 BD2), which are considered to be responsible for binding chromatin. protein specifically recognizes histone H4 tail at Lys12. Here, we report crystal structure...
The activation of the nuclear factor erythroid 2-related 2 (Nrf2) transcription function has been implicated in protection neurodegenerative diseases. cytoplasmic protein, Kelch-like ECH-associated protein 1 (Keap1), negatively regulates Nrf2. Keap1-Nrf2 pathway is a potential therapeutic target for tackling free-radical damage. Dimethyl fumarate (DMF) currently an approved drug treatment relapsing multiple sclerosis. Recent studies showed that DMF modifies reactive cysteines BTB domain...
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe disease. SARS-CoV-2 responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available treatment COVID-19, discovering potent inhibitors urgently required benefit humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through...
The assembly of core histones onto eukaryotic DNA is modulated by several histone chaperone complexes, including Asf1, CAF-1, and HIRA. Asf1 a unique that participates in both the replication-dependent replication-independent pathways. Here we report crystal structures apo-form fission yeast Asf1/Cia1 (SpAsf1N; residues 1-161) as well its complexes with B-domain HIRA orthologue Hip1 (Hip1B) C-terminal region Cac2 subunit CAF-1 (Cac2C). mode Asf1N-Hip1B recognition similar to human Asf1-HIRA...
Muscle diseases are clinically and genetically heterogeneous manifest as dystrophic, inflammatory myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration inflammation linked muscle pathology with mitochondrial damage oxidative stress. In this study, we investigated whether human display changes. biopsies from disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory 24), distal...
Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants have toxic-gain of function by destabilizing the functional homodimer, consequently inducing fibril-like aggregation cytotoxic non-native trimer intermediate. Therefore, reducing oligomerization via chemical modulators an optimal therapy ALS. Here, we report discovery...
The Nrf2 transcription factor, which plays important roles in oxidative and xenobiotic stress, is negatively regulated by the cytoplasmic repressor Keap1. beta-propeller/Kelch domain of Keap1, formed double-glycine repeat C-terminal region domains (Keap1-DC), interacts directly with Neh2 Nrf2. nuclear oncoprotein prothymosin alpha (ProTalpha) also Keap1 may play a role dissociation Keap1-Nrf2 complex. structure Keap1-DC complexed ProTalpha peptide (amino acids 39-54) has been determined at...
BRD4, which is a member of the BET (bromodomains and extraterminal) protein family, interacts preferentially with acetylated chromatin possesses multiple cellular functions in meiosis, embryonic development, cell cycle, transcription. BRD4 its family members contain two bromodomains known to bind lysine, conserved ET domain whose function unclear. Here we show solution structure mouse provides first three-dimensional an family. We determined NMR BRD4-ET root-mean-square deviation 0.41 A for...
The BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of host. structural mechanism for how N-terminal bromodomain human BRD2 (BRD2-BD1) deciphers mono-acetylated status histone H4 tail was recently reported. Here we show crystal structure second (BRD2-BD2) in complex with di-acetylated (H4K5ac/K12ac). To our surprise, a single K5ac/K12ac peptide interacts BRD2-BD2...
Abstract Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP + ) 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII compared CI Manganese (Mn) neurotoxicity....
Abstract Highly specific peptide structures can be designed by inserting dehydro residues into sequences. The N‐Boc‐ L ‐Phe‐dehydro‐Phe‐ ‐Val‐ ‐Val‐OCH 3 , synthesized conventional procedures, crystallizes from methanol‐‐water mixtures at 4°C in the tetragonal space group P4 with cell parameters a = b 13.829 ± 0.003 Å, c 27.587 0.008 V 5275.5 0.2 Å Z 4, d m 1.152 0.005 g cm −3 cal 1.150 . overall residual factor R 0.084 for 2342 reflections, 2θ max 140° using CuKα radiation. backbone torsion...
Oxidative damage has been associated with various neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's as well non-neurodegenerative conditions such cancer heart disease.The Keap1-Nrf2 system plays a central role in the protection of cells against oxidative xenobiotic stress.The Nrf2 transcription function its degradation by proteasomal pathway (Keap1-Nrf2-Cul3-Roc1 complex) are regulated cytoplasmic repressor protein, Keap1 which...
Cu/Zn superoxide dismutase-1 (SOD1) mutations are causative for a subset of amyotrophic lateral sclerosis (ALS) cases. These lead to structural instability, aggregation and ultimately motor neuron death. We have determined crystal structures SOD1 in complex with naphthalene-catechol-linked compound which binds low micro-molar affinity site important oxidative damage-induced aggregation. Trp32 oxidation is indeed significantly inhibited by ligand binding. Our work shows how linking can be...
The cytoplasmic repressor Keap1 regulates the function of transcription factor Nrf2 which plays critical roles in oxidative and xenobiotic stresses. Neh2 domain interacts with at bottom region Kelch/beta-propeller is formed by double-glycine repeat C-terminal domains (Keap1-DC). structure Keap1-DC complexed an peptide containing a conserved DLG motif has been determined 1.9 A resolution. Keap1-bound possesses hairpin conformation, it binds to protein beta-propeller domain. intermolecular...
Abstract Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with dysfunction, which turn entailed altered proteome proteins. Proteomic identification oxidized proteins biopsies from muscular dystrophy patients revealed specific to be targeted for oxidation. These included respiratory complexes displayed modification Trp residues different subunits. Among these, Ubiquinol-Cytochrome C...