A5009113005- Lipid Membrane Structure and Behavior
- Drug Transport and Resistance Mechanisms
- DNA and Nucleic Acid Chemistry
- Hearing, Cochlea, Tinnitus, Genetics
- Ion channel regulation and function
- Cholesterol and Lipid Metabolism
- Neuroscience and Neuropharmacology Research
- RNA and protein synthesis mechanisms
- Electrospun Nanofibers in Biomedical Applications
- Mechanical stress and fatigue analysis
- Particle accelerators and beam dynamics
- RNA Interference and Gene Delivery
- Nanopore and Nanochannel Transport Studies
- Acoustic Wave Phenomena Research
- Erythrocyte Function and Pathophysiology
- Advanced biosensing and bioanalysis techniques
- Protein Structure and Dynamics
- Spectroscopy and Quantum Chemical Studies
- Electron Spin Resonance Studies
- Photosynthetic Processes and Mechanisms
- Protein Interaction Studies and Fluorescence Analysis
- Pediatric Hepatobiliary Diseases and Treatments
- Sphingolipid Metabolism and Signaling
- Photoreceptor and optogenetics research
- Ion Transport and Channel Regulation
University of Illinois Urbana-Champaign
2019-2025
Novartis Institutes for BioMedical Research
2023
Moderna Therapeutics (United States)
2023
Novartis (Switzerland)
2023
International University of the Caribbean
2022
Urbana University
2020-2021
Institute of Theoretical and Experimental Biophysics
2017
Forschungszentrum Jülich
2017
Stadtwerke Jülich (Germany)
2017
Sharif University of Technology
2017
Abstract The initial step in the sensory transduction pathway underpinning hearing and balance mammals involves conversion of force into gating a mechanosensory channel 1 . Despite profound socioeconomic impacts disorders fundamental biological significance understanding transduction, composition, structure mechanism complex have remained poorly characterized. Here we report single-particle cryo-electron microscopy native transmembrane channel-like protein (TMC-1) isolated from...
Molecular dynamics (MD) simulations of biological membranes have achieved such levels sophistication that are commonly used to predict unresolved structures and various properties lipids substantiate experimental data. While achieving sufficient sampling lipid remains a major challenge, method improve sampling, e.g., in terms specific interactions with membrane-associated proteins, is randomize the initial arrangement constituents multiple replicas simulations, without changing overall...
ABCG2 is an ATP-binding cassette (ABC) transporter that extrudes a wide range of xenobiotics and drugs from the cell contributes to multidrug resistance in cancer cells. Following our recent structural characterization topotecan-bound ABCG2, here, we present cryo-EM structures under turnover conditions complex with special modulator slow substrate, tariquidar, nanodiscs. The reveal similar topotecan, tariquidar induces two distinct conformations (turnover-1 turnover-2). μs-scale molecular...
Lipid nanoparticles (LNPs) containing ionizable aminolipids are among the leading platforms for successful delivery of nucleic-acid-based therapeutics, including messenger RNA (mRNA). The two recently FDA-approved COVID-19 vaccines developed by Moderna and Pfizer/BioNTech belong to this category. Ionizable aminolipids, cholesterol, DSPC lipids key components such formulations, crucially modulating physicochemical properties these formulations and, consequently, potency therapeutics. Despite...
Spinster (Spns) lipid transporters are critical for transporting sphingosine-1-phosphate (S1P) across cellular membranes. In humans, Spns2 functions as the main S1P transporter in endothelial cells, making it a potential drug target modulating signaling. Here, we employed an integrated approach membranes to identify unknown conformational states of bacterial Spns from Hyphomonas neptunium (HnSpns) and define its proton- substrate-coupled dynamics. Our systematic study reveals conserved...
Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of underlying substrate interactions and transport mechanisms remain poorly resolved at molecular level. Here we report cryo-EM structures lipid-embedded human ABCA7 in an open state a nucleotide-bound, closed resolutions between 3.6 4.0 Å. The former reveals ordered patch bilayer lipids traversing transmembrane domain (TMD), while latter lipid-free, TMD with small...
Abstract Chloride homeostasis is regulated in all cellular compartments. CLC-type channels selectively transport Cl − across biological membranes. It proposed that side-chains of pore-lining residues determine selectivity channels, but their spatial orientation and contributions to are not conserved. This suggests a possible role for mainchain amides selectivity. We use nonsense suppression insert α-hydroxy acids at positions two CLC-0 bCLC-k, thus exchanging peptide-bond with ester-bond...
Abstract Prestin is a high-density motor protein in the outer hair cells (OHCs), whose conformational response to acoustic signals alters shape of cell, thereby playing major role sound amplification by cochlea. Despite recent structures, prestin’s intimate interactions with membrane, which are central its function remained unresolved. Here, employing large set (collectively, more than 0.5 ms) coarse-grained molecular dynamics simulations, we demonstrate impact lipid-protein on organization...
KRAS-4B regulates cellular proliferation and differentiation via its GTPase activity, it is often mutated in human tumors. Deregulation of the MAPK/ERK pathway as a result K-Ras4B mutations leads to uncontrolled proliferation, with dimer/multimerization on plasma membrane believed be initiating event for subsequent signaling. While proteins are known cluster membrane, whether they associate through well-defined dimerization interfaces remains an open question. Here, we present landscape...
Particles with internal degrees of collective self-propulsion – modelled as an ensemble self-propelled rods show complex motility behaviour, such random walks, persistent motion, circling, and run-and-circle motion.
P‐glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide‐binding domains (NBDs) drive transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate hydrolysis‐induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations NBDs APO system, are simulated. exchange induces mostly within conserved signature motif NBDs, resulting relative orientational...
Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them anchor biological membranes, switch their subcellular localization, and modulate association with other proteins. Such thus crucial for multiple processes including signal transduction, trafficking, membrane localization implicated in various diseases as well. Examples of lipid-anchored proteins include the Ras family undergo farnesylation; actin gelsolin...
Phosphatidylinositol-3-kinase Alpha (PI3Kα) is a lipid kinase which regulates signaling pathways involved in cell proliferation. Dysregulation of these promotes several human cancers, pushing for the development anticancer drugs to target PI3Kα. One such medicinal chemistry campaign at Novartis led discovery BYL719 (Piqray, Alpelicib), PI3Kα inhibitor approved by FDA 2019 treatment HR+/HER2-advanced breast cancer with PIK3CA mutation. Structure-based drug design played key role compound and...
ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their in vitro modulation purified ABCG2, report four high-resolution cryo-EM structures computational analyses elucidate interactions with ABCG2. We found derivatives are based on ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In...
Summary The initial step in the sensory transduction pathway underpinning hearing and balance mammals involves conversion of force into gating a mechanosensory (MT) channel. Despite profound socioeconomic impacts disorders fundamental biological significance understanding MT, composition, structure mechanism MT complex has remained elusive. Here we report single particle cryo-EM native TMC-1 isolated from C. elegans . 2-fold symmetric is composed 2 copies each pore-forming subunit,...
Abstract Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of underlying substrate interactions and transport mechanisms remain poorly resolved at molecular level. Here we report cryo-EM structures lipid-embedded human ABCA7 in an open state a nucleotide-bound, closed resolutions between 3.6-4.0 Å. The former reveals ordered patch bilayer lipids traversing transmembrane domain (TMD), while latter lipid-free, TMD with small...
Abstract The initial step in the sensory transduction pathway underpinning hearing and balance mammals involves conversion of force into gating a mechanosensory (MT) channel. Despite profound socioeconomic impacts disorders fundamental biological significance understanding MT, composition, structure mechanism MT complex has remained elusive. Here we report single particle cryo-EM native TMC-1 isolated from C. elegans. 2-fold symmetric is composed 2 copies each pore-forming subunit,...