This Project Grant award from the National Institute on Drug Abuse (NIDA) under the Drug Use and Addiction Research Programs (CFDA 93.279) provides $480,000 to Baylor College of Medicine to develop tools for dynamics-based drug discovery of receptors for drugs of abuse. The project aims to generate chemical biology tools to enable time-resolved cryogenic electron microscopy of G protein-coupled receptors (GPCRs) interacting with their signaling partners. This will be complemented by developing a...
The National Institute of General Medical Sciences (NIGMS) awarded a $377,123 Project Grant under the Biomedical Research and Research Training program (CFDA 93.859) to The Research Foundation For The State University Of New York (RF SUNY) to conduct research on the structural and mechanistic bases for ligand specificity of A1-adrenergic receptors (A1-ARs). The project aims to use cryo-electron microscopy, biochemical and cellular studies to gain structural and mechanistic insights into A1-AR...
This $399,884 Project Grant award from the National Institute on Drug Abuse (NIDA) under the Drug Use and Addiction Research Programs (CFDA 93.279) aims to identify small molecule compounds that can bind to the GPR26 receptor, which is believed to be a novel target for treating opioid use disorders. The research strategy involves using DNA-encoded library (DEL) screening technology to efficiently test over 125 million novel compounds and identify high-affinity binders to GPR26 that can...
This federal Project Grant award from the National Institute of General Medical Sciences (NIGMS, CFDA 93.859 Biomedical Research and Research Training program) provides $445,000.00 in funding to the Beckman Research Institute of the City of Hope to conduct research on the structural biology and allosteric communication of G protein-coupled receptors (GPCRs) and G proteins. The key research objectives are to: 1) Dissect the structural basis of allosteric modulation by the third intracellular loop...
This federal Project Grant award of $390,000.00, provided by the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859), supports research into the structural dynamics of G protein-coupled receptor (GPCR) oligomerization and its impact on GPCR localization and signaling. The award, spanning August 1, 2025 to July 31, 2030, will be performed by The Medical College of Wisconsin, Inc. (MCW), a private non-profit medical...
The University of Pittsburgh was awarded a $376,902 project grant by the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training (CFDA 93.859) federal grant program. The grant supports research on the mechanisms by which alpha-arrestin proteins regulate protein trafficking in cells. The research aims to provide a deep, mechanistic understanding of how alpha-arrestins recognize cargo proteins and control their localization across cellular...
This Project Grant award from the National Institute on Drug Abuse (NIDA) under the Drug Use and Addiction Research Programs (CFDA 93.279) provides $139,998 in funding to the Regents of the University of Minnesota to elucidate the cellular and neurochemical mechanisms underlying cocaine-induced suppression of inhibitory G protein-coupled receptor signaling in the prelimbic cortex. The goal is to investigate therapeutic interventions to restore this signaling pathway and mitigate aberrant...
This $455,824.20 Project Grant from the National Center for Advancing Translational Sciences will fund research to identify direct interactions between understudied G protein-coupled receptors (GPCRs) and protein kinase A (PKA) isoforms. The University of Utah will utilize the National Institutes of Health's existing Prestwick Chemical Library and NanoBRETT kinase assay platforms to develop a high-throughput screening assay for GPCR-PKA interactions. This assay will then be applied to...
This Project Grant award from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training program (CFDA 93.859) will provide $108,793 to the University of Chicago to support structural and functional characterization of Cadherin EGF Laminin G Seven-Pass G-Type Receptors (Celsrs or Adgrcs), a family of adhesion G protein-coupled receptors (AGPCRs) that are essential for animal development. The research aims to determine the structural basis for...
Under a $368,673 Project Grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) awarded on September 25, 2023, Artiam Bio Inc., a minority-owned small disadvantaged biotechnology company, is developing and evaluating second-generation partial inverse agonists targeting the type 1 cannabinoid (CB1) receptor as a potential therapy for alcohol use disorder (AUD). Artiam Bio is conducting preclinical efficacy studies of its lead CB1 receptor partial inverse agonist compound in rat...
ENTROPIC REDISTRIBUTION DRIVES THE GRK-INDEPENDENT BINDING OF ARRESTIN 2 TO THE CANNABINOID 2 RECEPTOR - CONTACT PD/PI: SHRIVER, THOMAS J. PROJECT SUMMARY ARRESTINS ARE AN IMPORTANT CLASS OF SECONDARY MESSENGER PROTEINS INVOLVED IN SIGNAL TRANSDUCTION AT G PROTEIN- COUPLED RECEPTORS (GPCRS) THROUGHOUT THE HUMAN BODY. THEY UNDERPIN CASCADES ASSOCIATED WITH NOCICEPTION, PLANNING, MOOD REGULATION, ANXIETY, AND DEPRESSION - ALL HIGHER ORDER FUNCTIONS MISREGULATED IN INDIVIDUALS WITH ADDICTION DISORDERS. DESPITE ARRESTINS' INVOLVEMENT IN MANY CLINICALLY IMPORTANT PROCESSES, OUR UNDERSTANDING OF THEIR FUNCTION ON A MOLECULAR BASIS STILL LAGS BEHIND THE "CANONICAL" SECONDARY MESSENGERS AT GPCRS, G PROTEINS. THIS IS DUE IN LARGE PART TO THE COMPLICATED REGULATION AND ACTIVITY OF ARRESTINS, WHICH WERE INITIALLY THOUGHT TO SIMPLY DOWNREGULATE GPCR SIGNALING THROUGH ENDOCYTOSIS. A FAR MORE SOPHISTICATED VIEW HAS EVOLVED IN RECENT YEARS, SHOWING THAT AN INTERPLAY BETWEEN EXTRACELLULAR LIGAND, RECEPTOR, LOCAL MEMBRANE ENVIRONMENT, AND INTRACELLULAR KINASES (GRKS) ALL PLAY A ROLE IN DIRECTING ARRESTIN RECRUITMENT. DUE TO THE MULTICOMPONENT NATURE OF THESE INTERACTIONS AND THEIR INHERENTLY DYNAMIC NATURE, STRUCTURAL STUDIES REVEALING THE DETAILED MOLECULAR WORKINGS OF ARRESTIN SIGNALING REGULATION HAVE BEEN CUMBERSOME. RECENT ADVANCES IN NUCLEAR MAGNETIC RESONANCE (NMR) HAVE ENABLED HIGH RESOLUTION STRUCTURES OF SOME GPCR/ARRESTIN COMPLEXES, BUT A SIGNIFICANT BARRIER REMAINING IS RECAPITULATING THE COMPLEX REGULATION OF ARRESTIN RECRUITMENT VIA GRKS. THE SPATIAL AND TEMPORAL RESOLUTION OF GRK PHOSPHORYLATION ALLOWS THESE RECEPTORS TO FINE TUNE THEIR SELECTION OF ARRESTIN SIGNALING PATHWAY BUT ALSO CREATES AN INCREDIBLY COMPLICATED LANDSCAPE FOR STRUCTURAL BIOLOGISTS. THIS DIFFICULTY IS LESSENED IF GRKS ARE NOT ALWAYS REQUIRED FOR ARRESTIN RECRUITMENT, AN IDEA THAT IS FINDING TRACTION WITHIN THE GPCR COMMUNITY. RECENT STUDIES HAVE SHOWN THAT THE CANNABINOID 2 RECEPTOR (CB2R) CAN RECRUIT ARRESTINS IN GRK KNOCK-DOWN CELL LINES AND THAT THIS RECRUITMENT IS SENSITIVE TO MUTATIONS IN ACIDIC GLUTAMATE AND ASPARTATE RESIDUES WITHIN THE RECEPTOR C-TERMINUS. REMOVAL OF THE PUTATIVE REQUIREMENT OF GRKS WILL FACILITATE NMR TECHNIQUES UNIQUELY CAPABLE OF DELINEATING THE INDIVIDUAL MOLECULAR COMPONENTS AND DYNAMICS OF THE INTERACTIONS BETWEEN GPCRS AND ARRESTINS. SUCH TECHNIQUES WILL REQUIRE ADVANCED STATISTICAL TREATMENT WHICH IS ACCESSIBLE TO ME THROUGH MULTIPLE NORTHWESTERN CLASSES. MY PROJECT SEEKS TO SHOW THAT CB2R IS A SUITABLE TARGET FOR THIS SIMPLIFICATION STRATEGY AND THAT THIS METHODOLOGY IS TRANSLATIONAL IN NATURE, ALLOWING SIMILAR APPROACHES AT OTHER GPCR TARGETS. I HYPOTHESIZE THAT THERE EXISTS A SPECTRUM OF GRK DEPENDENCE FOR ARRESTIN RECRUITMENT ACROSS GPCR PHYLOGENY, ENABLING A REDUCTION IN SYSTEM COMPLEXITY FOR BIOCHEMICAL STUDY THROUGH APPROPRIATE RECEPTOR SELECTION. AN UNDERSTANDING OF SUCH INTERACTIONS MAY EVENTUALLY ALLOW THE DEVELOPMENT OF NOVEL PHARMACEUTICALS DESIGNED USING DYNAMICS-INFORMED STRUCTURAL APPROACHES.