A5045542300- Enzyme Structure and Function
- Protein Structure and Dynamics
- Eosinophilic Disorders and Syndromes
- Fibroblast Growth Factor Research
- Chronic Myeloid Leukemia Treatments
- Protein purification and stability
- Advanced NMR Techniques and Applications
- Protein Kinase Regulation and GTPase Signaling
- Molecular spectroscopy and chirality
- Biosimilars and Bioanalytical Methods
- Mass Spectrometry Techniques and Applications
- Quinazolinone synthesis and applications
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Chronic Lymphocytic Leukemia Research
- Viral Infectious Diseases and Gene Expression in Insects
- RNA and protein synthesis mechanisms
- Amino Acid Enzymes and Metabolism
- Protein Tyrosine Phosphatases
- Pharmaceutical studies and practices
- Biochemical and Molecular Research
- Analytical Chemistry and Chromatography
- Lipid Membrane Structure and Behavior
- Opportunistic and Delay-Tolerant Networks
- Nuclear physics research studies
Biocon (India)
2020-2025
AstraZeneca (United Kingdom)
2015-2016
University of Basel
2006-2013
AstraZeneca (Singapore)
2013
Salk Institute for Biological Studies
2012
ETH Zurich
2012
Institut de Biologie Structurale
2006-2010
Université Joseph Fourier
2010
Université Grenoble Alpes
2006-2010
Centre National de la Recherche Scientifique
2010
Current structural understanding of kinases is largely based on x-ray crystallographic studies, whereas very little data exist the conformations and dynamics that adopt in solution state. ABL kinase an important drug target treatment chronic myelogenous leukemia. Here, we present first characterization complex with three clinical inhibitors (imatinib, nilotinib, dasatinib) by modern NMR techniques. Structural dynamical results were derived from complete backbone resonance assignments,...
Abstract Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp–Phe–Gly (DFG) motif activation loop, with some, including FGFR1 kinase, appearing refractory this so-called ‘DFG flip’. Recent inhibitor-bound structures have unexpectedly revealed for first time a ‘DFG-out’ state. Here we use conformationally selective inhibitors as chemical probes interrogation structural and dynamic features that appear govern DFG flip FGFR1. Our detailed...
Proteins denature not only at high, but also low temperature as well high pressure. These denatured states are easily accessible for experiment, because usually heat denaturation causes aggregation, whereas cold or pressure occurs temperatures below the freezing point of water pressures above 5 kbar, respectively. Here we have obtained atomic details pressure-assisted, cold-denatured state ubiquitin 2,500 bar and 258 K by high-resolution NMR techniques. Under these conditions, a folded,...
Residual dipolar couplings (RDCs) observed by NMR in solution under weak alignment conditions can monitor average net orientations and order parameters of individual bonds. By their simple geometrical dependence, RDCs bear particular promise for the quantitative characterization conformations partially folded or unfolded proteins. We have systematically investigated influence amino acid substitutions X on conformation model peptides EGAAXAASS as monitored (1)H(Nu)-(15)N...
Current NMR information on side-chain conformations of unfolded protein states is sparse due to the poor dispersion particularly proton resonances. We present here optimized schemes for detection 3JHαHβ, 3JNHβ, and 3JC′Hβ scalar 1DCβHβ residual dipolar couplings (RDCs) in proteins. For urea-denatured ubiquitin G, up six 3J-couplings 1Hβ are detected, which define χ1 angle at very high precision. Interpretation 3J by a model mixed staggered rotamers yields excellent agreement also provides...
The integrity of a higher order structure (HOS) is an essential requirement to ensure the efficacy, stability, and safety protein therapeutics. Solution-state nuclear magnetic resonance (NMR) occupies unique niche as one most promising methods access atomic-level structural information on soluble biopharmaceutical formulations. Another major class drugs poorly soluble, such microcrystalline suspensions, which poses significant challenges for characterization active ingredient in its native...
Abstract Protein kinases are highly dynamic and complex molecules. Here we present high‐pressure relaxation studies of the activated p38α mitogen‐activated protein kinase (MAPK). plays a central role in inflammatory diseases such as rheumatoid arthritis is therefore attractive pharmaceutical target. The combination high pressure NMR spectroscopy allowed for detailed per‐residue based assessment structural plasticity accessibility low‐lying excited‐energy conformations throughout structure....
Insulin glargine is a long-acting analogue of human insulin that has been used to manage hyperglycemia in patients with diabetes mellitus (DM) for nearly 20 years. relatively constant concentration-time profile mimics basal levels and allows once-daily administration. MYL-1501D biosimilar designed offer greater access patients, comparable efficacy safety the marketed reference product. We conducted comprehensive panel studies based on formal analysis critical quality attributes characterize...
Abstract The cycling between GDP- and GTP- bound forms of the Ras protein is partly regulated by binding Sos. structural/dynamic behavior complex formed activated Sos at point functional cycle where nucleotide exchange completed has not been described to date. Here we show that solution NMR spectra H-Ras∙GTPγS mixed with a fragment (Sos Cat ) 2:1 ratio are consistent formation rather dynamic assembly. was in fast on timescale retained significant degree molecular tumbling independent , while...
The current trend in the biopharmaceutical market has boosted development and production of biological drugs with high efficacy fidelity for receptor binding. While high-resolution structural insights into binding epitopes are indispensable better therapeutic design, it is tedious costly. In this work, we develop a protocol by integrating two well-known NMR-based solution-state methods. Saturation transfer double-difference methyl-TROSY (STDD-Methyl TROSY NMR) was used to probe methyl ligand...