A5047875895- Receptor Mechanisms and Signaling
- Protein Structure and Dynamics
- Neuropeptides and Animal Physiology
- Mass Spectrometry Techniques and Applications
- Neuroendocrine regulation and behavior
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Stress Responses and Cortisol
- Pharmacogenetics and Drug Metabolism
- Photosynthetic Processes and Mechanisms
- Hypothalamic control of reproductive hormones
- Sleep and Wakefulness Research
- Metal-Catalyzed Oxygenation Mechanisms
- Evolution and Genetic Dynamics
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Atmospheric Ozone and Climate
- Advanced Proteomics Techniques and Applications
- RNA and protein synthesis mechanisms
- Ion channel regulation and function
- SARS-CoV-2 and COVID-19 Research
- Cellular Mechanics and Interactions
- Monoclonal and Polyclonal Antibodies Research
Bristol-Myers Squibb (United States)
2023-2025
Merck & Co., Inc., Rahway, NJ, USA (United States)
2020-2024
Stanford University
2018-2021
Stanford Medicine
2021
University of California, Irvine
2013-2017
Jeffrey Modell Foundation
2015
Oregon State University
2009-2011
Biotechnology and Biological Sciences Research Council
1989
Babraham Institute
1988
Jichi Medical University
1988
The Ramachandran plot is among the most central concepts in structural biology, seen publications and textbooks alike. However, with increasing numbers of known protein-structures greater accuracy ultra-high resolution protein structures, we are still learning more about basic principles structure. Here use high fidelity conformational information to explore novel ways, such a geo-style wrapped plots, convey some aspects conformation. We point out pressing need for standard nomenclature...
Abstract Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain’s ability to control sleep-wake cycles. Current therapies are limited management of symptoms with modest effectiveness and substantial adverse effects. Agonists orexin receptor 2 (OX R) have shown promise as novel therapeutics directly target pathophysiology disease. However, identification drug-like OX R agonists has proven difficult. Here we report cryo-electron microscopy structures active-state...
Abstract Lung fibrosis, or the scarring of lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis worse than most types cancer. We previously discovered that MK-0429 an equipotent pan-inhibitor αv integrins reduces proteinuria kidney fibrosis in preclinical model. In present study, we further demonstrated significantly inhibits progression bleomycin-induced lung injury search newer integrin inhibitors for characterized monoclonal...
Significance Activation of G protein-coupled receptors (GPCRs) initiates conformational shifts that trigger interaction with a specific G-protein subtype from structurally homologous set. A major unsolved problem is the mechanism by which this selectivity achieved. Structures GPCR–G protein complexes so far fail to reveal origin because they all involve one (G s ). In work, we report structural model activated GPCR rhodopsin in complex another i ) derived intermolecular distance mapping...
Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanisms by which remain elusive, however, given recent structures that reveal similar binding sites across Here we show positive (PAMs) of the M1 muscarinic acetylcholine (mAChR) exquisite occupying a dynamic pocket absent in existing crystal structures. This cryptic forms far more...
Abstract The number of structures and molecular dynamics simulations proteins is exploding owing to dramatic advances in cryo-electron microscopy, crystallography, computing. One the most powerful ways analyze structural information involves comparisons interatomic interactions across different or same protein related from family ( e.g. GPCRs). Such comparative analyses are interest a wide range researchers but currently prove challenging for all few. To facilitate analyses, we have...
Blood samples were taken from conscious, chronically-catheterized rats during parturition for measurement of oxytocin by specific radioimmunoassay. After the birth 3rd pup, allowed to remain in their nesting cage (undisturbed rats) or transferred 45 min a glass bowl (disturbed rats); at time transfer, given an i.v. injection opioid antagonist naloxone saline vehicle. Subsequent was prolonged saline-treated disturbed rats, but not naloxone-treated rats. Parturition significantly hastened...
Significance Cytochrome P450 activates molecular oxygen to hydroxylate various molecules. This process requires the transfer of electrons from a redox partner, which further formation specific protein–protein complex. A question increasing importance is whether or not interaction between and its partner results in functionally important structural changes required for activity. The present work addresses favors binding conformer. critically understanding how P450s activate oxygen.
Abstract Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue limit true therapeutic potential related agents. dimers were synthesized investigate whether partial agonism receptor (IR) tyrosine kinase is achievable, and explore for tissue-selective systemic pharmacology. The...
Significance Structure-based drug design depends on the ability to predict both three-dimensional structures of candidate molecules bound their targets and associated binding affinities. We demonstrate that one can substantially improve accuracy these predictions using easily obtained data about completely different bind same target without requiring any target-bound molecules. The approach we developed integrate physical data-driven modeling may find a variety applications in rapidly...
Plasma samples were obtained before and during parturition from conscious rats implanted chronically with a jugular cannula. Rats either allowed to remain in their nesting cage throughout parturition, or moved immediately following the birth of second third pup into an empty glass chamber. The time-course was prolonged for mother which mid-parturition this unfamiliar environment. However, given i.v. injection opioid antagonist naloxone at time transfer, followed normal time-course, plasma...
An initial series of NLRP3 agonist antibody-drug conjugates (ADCs) failed to induce IL-1β in vitro due lysosomal trapping the payload. To address this, we developed assays and computational tools identify a new payload that could diffuse out lysosomes. ADCs derived from this were active, emphasizing need avoid accumulation for nonlysosomal targets. Two active necessitated attaching cleavable valine-citrulline recognition element via noncanonical ester linkage, rather than canonical carbamate...
Linear groups-polypeptide conformations based on a single repeating phi,psi-pair-are foundational concept in protein structure, yet how they are presented textbooks is largely theoretical studies from the early days of structure analysis. Now, ultra-high resolution structures provide resource for an accurate empirical and systematic assessment linear groups that truly exist proteins. Here, purely conformation-based survey shows only three distinct phi,psi-regions occur: diverse set extended...
Biased agonists, which selectively stimulate certain signaling pathways controlled by a G protein-coupled receptor (GPCR), hold great promise as drugs that maximize efficacy while minimizing dangerous side effects. agonists of the μ-opioid (μOR) are particular interest means to achieve analgesia through protein without dose-limiting effects such respiratory depression and constipation. Rational structure-based design biased remains highly challenging, however, because ligand-mediated...
Toll-like receptors 7 and 8 are involved in modulating the adaptive innate immune responses, their activation has shown promise as a therapeutic strategy field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result poor tolerance, combination therapies targeted delivery through antibody–drug conjugates (ADCs) help mitigate adverse effects. Described herein is identification novel potent series pyrazolopyrimidine-based with tunable receptor selectivity. Representative from...
Abstract Coronaviruses have been the causative agent of three epidemics and pandemics in past two decades, including ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent treat COVID-19, but also provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on viral surface enter host cells, these share sequence structural homology, we set out discover cross-reactive biologic...
Cytochrome P450cam catalyzes the stereo and regiospecific hydroxylation of camphor to 5-exo-hydroxylcamphor. The two electrons for oxidation are provided by putidaredoxin (Pdx), a Fe2 S2 containing protein. Two recent crystal structures P450cam-Pdx complex, one solved with aid covalent cross-linking without, have structural picture redox partner interaction. To study stability complex structure minor differences between structures, 100 nanosecond molecular dynamics (MD) simulation...
Nitric oxide synthase (NOS) is a multidomain enzyme that catalyzes the production of nitric (NO) by oxidizing L-Arg to NO and L-citrulline. requires multiple interdomain electron transfer steps between flavin mononucleotide (FMN) heme domain. Specifically, NADPH-derived electrons are transferred heme-containing oxygenase domain via adenine dinucleotide (FAD) FMN containing reductase domains. While crystal structures available for both domains NOS, date there no atomic level structural...