A5047533207- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Neuropeptides and Animal Physiology
- Lipid Membrane Structure and Behavior
- Cellular transport and secretion
- Mass Spectrometry Techniques and Applications
- Adenosine and Purinergic Signaling
- Lysosomal Storage Disorders Research
- Cholesterol and Lipid Metabolism
- SARS-CoV-2 and COVID-19 Research
- Protein Kinase Regulation and GTPase Signaling
- Diabetes Treatment and Management
- Protein Structure and Dynamics
- Spectroscopy and Quantum Chemical Studies
- Pharmacological Receptor Mechanisms and Effects
- Biomedical Research and Pathophysiology
- Bacteriophages and microbial interactions
- Photoreceptor and optogenetics research
- Ion channel regulation and function
- Crystallization and Solubility Studies
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Glycosylation and Glycoproteins Research
- HER2/EGFR in Cancer Research
- RNA and protein synthesis mechanisms
Monash University
2016-2025
The University of Melbourne
2021-2025
Walter and Eliza Hall Institute of Medical Research
2021-2025
Australian Research Council
2024
Peter Doherty Institute
2022
University of Michigan
2012-2019
Dabur (India)
2015
Sappasithiprasong Hospital
2015
Michigan United
2013
Lomonosov Moscow State University
2008
Significance Neutralizing antibodies are important for immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as therapeutics the prevention treatment of COVID-19. We identified high-affinity nanobodies SARS-CoV-2 receptor-binding domain found that nanobody cocktails consisting two noncompeting were able to block ACE2 engagement with RBD variants present in human populations potently neutralize both wild-type N501Y D614G variant at low concentrations. Prophylactic...
Recent technological advances and computational developments have allowed the reconstruction of Cryo-Electron Microscopy (cryo-EM) maps at near-atomic resolution. On a typical workflow once cryo-EM map has been calculated, sharpening process is usually performed to enhance visualization, step that proven very important in key task structural modeling. However, approaches, general, neglects local quality map, which clearly suboptimal.Here, new method for density proposed. The algorithm, named...
Advances in structural biology have yielded exponential growth G protein-coupled receptor (GPCR) structure solution. Nonetheless, the instability of fully active GPCR complexes with cognate heterotrimeric proteins has made them elusive. Existing structures been limited to nanobody-stabilized GPCR:Gs complexes. Here we present methods for enhanced GPCR:G protein complex stabilization via engineering reduced nucleotide affinity, limiting Gα:Gβγ dissociation. We illustrate application dominant...
The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding how different peptides generate profound differences G protein-mediated signalling still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, mutagenesis pharmacological assays, to interrogate the mechanism consequences binding four...
Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades research, molecular-level understanding the general principles that govern myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M 4 muscarinic acetylcholine receptor (M mAChR) validated and clinically relevant target for several psychiatric cognitive disorders. In this study, we rigorously quantified affinity, efficacy, magnitude two...
Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism reverse cholesterol transport, respectively. Whereas LPLA2 is predicted underlie the development drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease familial deficiency. Here we describe several high-resolution crystal structures human low-resolution structure...
Abstract The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding SecR binding activation is important its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, biochemical cross-linking to determine a 2.3 Å structure, interrogate bound the SecR:Gs complex. exhibited unique organization extracellular domain (ECD) relative 7-transmembrane (TM) core,...
Potent neutralizing monoclonal antibodies are one of the few agents currently available to treat COVID-19. SARS-CoV-2 variants concern (VOCs) that carry multiple mutations in viral spike protein can exhibit neutralization resistance, potentially affecting effectiveness some antibody-based therapeutics. Here, generation a diverse panel 91 human, provides an in-depth structural and phenotypic definition receptor binding domain (RBD) antigenic sites on spike. These RBD ameliorate infection mice...
The M
Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) familial LCAT deficiency (FLD). Herein we report the crystal structure of human in complex with a potent piperidinylpyrazolopyridine activator an acyl intermediate-like inhibitor, revealing active conformation. Unlike other activators, binds exclusively to membrane-binding domain (MBD). Functional studies indicate that compound does not modulate...
Abstract The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. precise mechanism the terminal steps pathway, where RIPK3 kinase phosphorylates triggers conformation change oligomerization effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation MLKL activation loop as cue for pseudokinase domain dimerization. dimerization...