A5007423068- PI3K/AKT/mTOR signaling in cancer
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Molecular Sensors and Ion Detection
- Machine Learning in Materials Science
- Chronic Lymphocytic Leukemia Research
- ATP Synthase and ATPases Research
- Melanoma and MAPK Pathways
- Mass Spectrometry Techniques and Applications
- Genetics and Neurodevelopmental Disorders
- Neonatal Health and Biochemistry
- Cardiac Imaging and Diagnostics
- Analytical Chemistry and Chromatography
- T-cell and B-cell Immunology
- Cytokine Signaling Pathways and Interactions
- Thyroid Disorders and Treatments
- HER2/EGFR in Cancer Research
- Hormonal Regulation and Hypertension
- Molecular spectroscopy and chirality
- Biochemical and Molecular Research
- Stress Responses and Cortisol
- Glycosylation and Glycoproteins Research
- Genetics, Bioinformatics, and Biomedical Research
Leidos (United States)
2015-2025
Frederick National Laboratory for Cancer Research
2015-2025
National Institutes of Health
2010-2024
Leidos Biomedical Research Inc. (United States)
2023
Johns Hopkins University
2015-2023
Johns Hopkins Medicine
2021
University of Baltimore
2020
National Cancer Institute
2015-2016
Research for Action
2010
National Institute of Diabetes and Digestive and Kidney Diseases
2010
RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with chaperone HSP90 cochaperone CDC37. Understanding intricate molecular interactions governing is crucial for comprehending this process. Here, we present a cryo-EM structure of closed-state RAF1-HSP90-CDC37 complex, where C-lobe kinase domain binds one side dimer, an unfolded N-lobe segment threads through center dimer. CDC37 C-lobe, mimicking HxNI motif. We also describe...
Glucocorticoids, major end effectors of the stress response, play an essential role in homeostasis central nervous system (CNS) and contribute to memory consolidation emotional control through their intracellular receptors, glucocorticoid mineralocorticoid receptors. Cyclin-dependent kinase 5 (CDK5), on other hand, plays important roles morphogenesis functions system, its aberrant activation has been associated with development neurodegenerative disorders. We previously reported that CDK5...
Human HRAS, KRAS, and NRAS genes encode four isoforms of Ras, a p21 GTPase. Mutations in KRAS account for the majority RAS-driven cancers. The has two splice variants, K-Ras4A K-Ras4B. Due to their reversible palmitoylation, N-Ras have bimodal signaling states. K-Ras4B differ catalytic domain residues (G151R/D153E/K165Q/H166Y) disordered C-terminal hypervariable region (HVR). In K-Ras4A, HVR is not as strongly positively charged (+6e vs +9e). Here, we performed all-atom molecular dynamics...
Molecular docking methods are widely used in drug discovery efforts. RAS proteins important cancer targets, and useful systems for evaluating methods, including accounting solvation effects covalent small molecule binding. Water often plays a key role binding to proteins, many inhibitors─including FDA-approved drugs─covalently bind oncogenic proteins. We assembled test set, consisting of 138 protein structures 2 KRAS DNA complex with ligands. In DOCK 6, we have implemented receptor...
Abstract Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific targets. MANAs HLA-presented (pHLA) peptides derived from intracellular mutant proteins that otherwise inaccessible antibody-based therapeutics. Here, we describe the cryo-EM structure an antibody-MANA pHLA complex. Specifically, determine TCR mimic (TCRm) antibody bound its MANA target, KRAS G12V...
Background: The sodium/iodide (Na+/I−) symporter (NIS) mediates active transport of I− into the thyroid gland. Mutations in SLC5A5 gene, which encodes NIS, cause defects (ITDs)—which, if left untreated, lead to congenital hypothyroidism and consequent cognitive developmental deficiencies. ITD-causing NIS mutation Y348D, located transmembrane segment (TMS) 9, was reported three Sudanese patients. Methods: We generated cDNAs coding for Y348D mutants with other hydrophilic hydrophobic amino...
To allow DOCK 6 access to unprecedented chemical space for screening billions of small molecules, we have implemented features from 3.7 into 6, including a search routine that traverses precomputed ligand conformations stored in hierarchical database. We tested them on the DUDE-Z and SB2012 test sets. The database is 16 times faster than anchor-and-grow. However, ability reproduce experimental pose 16% worse enrichment performance average similar, but has better 1.7 slower. with post-docking...
Molecular docking methods are widely used in drug discovery efforts. RAS proteins important cancer targets, and useful systems for evaluating methods, including accounting solvation effects covalent small molecule binding. Water often plays a key role binding to proteins, many inhibitors, approved drugs, covalently bind oncogenic proteins. We assembled test set, consisting of 138 protein structures 2 KRAS DNA complex with ligands. In DOCK 6, we have implemented receptor desolvation scoring...
Abstract The AAA+ ( A TPases a ssociated with variety of cellular ctivities) ATPase, Thorase, also known as ATAD1, plays multiple roles in synaptic plasticity, mitochondrial quality control and mTOR signaling through disassembling protein complexes like AMPAR mTORC1 an ATP-dependent manner. Oligomerization Thorase is crucial for its disassembly remodeling functions. We show that wild-type forms long helical filaments vitro , dependent on ATP binding but not hydrolysis. report the Cryogenic...
The Sodium/Iodide Symporter (NIS), a 13-helix transmembrane protein found in the thyroid and other tissues, transports iodide, required constituent of hormones T3 T4. Despite extensive experimental information clinical data, structural details intermediate microstates comprising conformational transition NIS between its inwardly outwardly open states remain unresolved. We present data from combination enhanced sampling path molecular dynamics (MD) simulations that elucidate principal to...
To allow DOCK 6 access to unprecedented chemical space for screening billions of small molecules, we have implemented features from 3.7 into 6, including a search routine that traverses precomputed ligand conformations stored in hierarchical database. We tested them on the DUDE-Z and SB2012 test sets. The database is 16 times faster than anchor-and-grow. However, ability reproduce experimental pose 16% worse enrichment performance average similar, but has better 1.7 slower. with post-docking...
Abstract Phosphatidylinositol 3,4,5-triphosphate (PIP3), a lipid second messenger, signals the initiation of cascades that result in, among other processes, cell proliferation, migration, and survival. PIP3 is generated by phosphorylation phosphatidylinositol 4,5-bisphosphate (PIP2) phosphoinositide-3-kinase-α (PI3Kα) in response to activation receptor tyrosine kinases (RTKs) or their substrates. PI3Kα has residual constitutive activity counteracted action PTEN, phosphatase subjected large...
ABSTRACT The Sodium/Iodide Symporter (NIS), a thirteen-helix transmembrane protein found in the thyroid and other tissues, transports iodide, required constituent of hormones T3 T4. Despite extensive experimental information clinical data, structural details intermediate microstates comprising conformational transition NIS between its inwardly outwardly open states remain unresolved. We present data from combination enhanced sampling path molecular dynamics (MD) simulations that elucidate...