A5069882505- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Pharmacological Effects and Assays
- Regulation of Appetite and Obesity
- Herpesvirus Infections and Treatments
- Hypothalamic control of reproductive hormones
- Cytomegalovirus and herpesvirus research
- Mass Spectrometry Techniques and Applications
- Nuclear Receptors and Signaling
- Apelin-related biomedical research
- Click Chemistry and Applications
- Biochemical Analysis and Sensing Techniques
- Chemical Synthesis and Analysis
- Plant Reproductive Biology
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Enzyme Structure and Function
- RNA regulation and disease
- Protease and Inhibitor Mechanisms
- Medical Coding and Health Information
- Studies on Chitinases and Chitosanases
- Lipid Membrane Structure and Behavior
- Biochemical and Structural Characterization
University of California, San Francisco
2021-2024
Heptares Therapeutics (United Kingdom)
2024
Vanderbilt University
2016-2023
Vanderbilt University Medical Center
2018
Harvard University
2012-2014
Apollo Instruments (United States)
2007
Herpesvirus nucleocapsids exit the host cell nucleus in an unusual process known as nuclear egress. The human cytomegalovirus (HCMV) UL97 protein kinase is required for efficient egress, which can be explained by its phosphorylation of lamina component lamin A/C, disrupts lamina. We found that a dominant negative A/C mutant complemented replication defect virus lacking dividing cells, validating this explanation. However, complementation was incomplete, we investigated whether HCMV egress...
As sequencing methodologies continue to advance, the availability of protein sequences far outpaces ability structure determination. Homology modeling is used bridge this gap but relies on high-identity templates for accurate model building. G-protein coupled receptors (GPCRs) represent a significant target class pharmaceutical therapies in which homology could fill knowledge structure-based drug design. To date, only about 17% druggable GPCRs have had their structures characterized at...
Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using homology model of difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated 4 (PAR4) is activated by thrombin cleavage, revealing tethered ligand that activates the receptor, making PAR4 challenging A screen make-on-demand chemical library yielded one-hit compound. From single-hit compound, developed novel series antagonists. Subsequent via simultaneous searches...
The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations allosteric modulation, and yet few drugs target them. This gap highlights the need for a deeper understanding modulation in GPCR drug discovery. current work introduces systematic annotation scheme to structurally classify binding sites based on class, transmembrane helix contacts, and, membrane-facing sites, membrane sublocation. specific was applied 107 bound by small...
ABSTRACT Protein-protein and protein-nucleic acid interactions within subcellular compartments are required for viral genome replication. To understand the localization of human cytomegalovirus replication factor UL84 relative to other proteins involved in DNA synthesis replicating infected cells, we created a recombinant virus expressing FLAG-tagged version (UL84FLAG) used this immunofluorescence assays. UL84FLAG differed at early late times infection, transitioning from diffuse...
Prerequisite for structural studies on G protein-coupled receptors is the preparation of highly concentrated, stable, and biologically active receptor samples in milligram amounts protein. Here, we present an improved protocol E. coli expression, functional refolding reconstitution into bicelles human neuropeptide Y type 2 (Y2R) solution solid-state NMR experiments. The isotopically labeled expressed inclusion bodies purified using SDS. We studied details including vitro folding receptor,...
ABSTRACT Protein-protein interactions are required for many biological functions. Previous work has demonstrated an interaction between the human cytomegalovirus DNA polymerase subunit UL44 and viral replication factor UL84. In this study, glutathione S -transferase pulldown assays indicated that residues 1 to 68 of UL84 both necessary sufficient efficient with in vitro . We created a mutant virus which sequences encoding these were deleted. This displayed decreased compared wild-type virus....
Membrane proteins are prone to misfolding and degradation. This is particularly true for mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Although they function at plasma membrane, GnRHRs accumulate within secretory pathway. Their apparent instability believed have evolved through selection attenuated GnRHR activity. Nevertheless, molecular basis this adaptation remains unclear. We show that coincides with a C-terminal truncation compromises translocon-mediated...
Fragment-based drug discovery begins with the identification of small molecules a molecular weight usually less than 250 Da which weakly bind to protein interest. This technique is challenging for computational docking methods as binding determined by only few specific interactions. Inaccuracies in energy function or slight deviations pose can lead prediction incorrect difficulties ranking fragments silico screening. Here, we test RosettaLigand series cysteine-depleted variant TIM-barrel...
Transmembrane protease, serine -2 (TMPRSS2) is an essential host entry factor in human airways for SARS-CoV-2 and influenza A/B has presented as a target antiviral drug development; however, no clinically viable, oral small molecule TMPRSS2 inhibitors have been developed to date. Here we perform two large-scale docking campaigns identify covalent noncovalent from homology model crystal structure. We establish pipeline rapidly screen inhibitors, then interrogate the potency, specificity...
Abstract We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, Elabela/Toddler (ELA), to regulate cardiovascular development function. Characterisation naturally occurring receptor variants from UK Genomics England 100,000 Genomes Project, AlphaFold2 modelling, identifies T89 2.64 as important in ELA binding site, R168 4.64 forming extensive interactions with C-termini both peptides. Base editing introduce an...
Abstract We describe a structural and functional study of the apelin receptor, G protein-coupled receptor (GPCR) that binds two endogenous peptide ligands, Elabela/Toddler (ELA), to regulate cardiovascular development function. Characterisation novel, naturally occurring variants from UK Genomics England 100,000 Genomes Project, in combination with AlphaFold2 modelling, identified T89 2.64 as an important residue ELA binding site, R168 4.64 forming extensive interactions C-termini both...