Emergent role of allostery on function of gpcrs and trimeric g proteins
Active Project Grant Awarded Last action
- Award ID
- R35GM156498
- Recipient
-
Beckman Research Institute Of The City Of Hope UEI NPH1VN32EWN5
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,290,500
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 34% complete
- Place of performance
- Irwindale, CA 91010, USA
Award details come from USAspending.gov.
Description
- Abstract
- The structural biology revolution in g protein coupled receptors (gpcrs) over the last two decades has pipelined a number of allosteric gpcr ligands into FDA clinical trials. Over 500 gpcr-g protein complexes are now publicly accessible and represent only the 'tip of the iceberg' of structures capturing ligand-gpcr-g protein complexes in biopharma. Despite this information explosion, these structures only provide static snap shots that do not capture the dynamic conformational landscape and allosteric communication that underlie the mechanism of drug action. Further, the quest of understanding the g protein coupling selectivity by gpcrs has necessitated enquiry into the role of sequence-divergent disordered structural regions of gpcrs that are not resolved in high-resolution structures. To address these challenges, we have developed innovative computational methods including AI centered techniques. Building on these new technologies and conceptual advances from my lab, we propose the following parallel research projects. (1) we have shown that the temporal coupling frequency of gpcr-g protein interactions and allosteric communication modulate the g protein coupling selectivity by gpcrs. Going forward we will dissect the structural basis of the allosteric modulation by the third intracellular loop (ICL3). We will define roles for ICL3 in autoregulation and g protein selection in closely related receptors. (2) our extensive studies in identifying allosteric hotspot residues in gpcrs involved in allosteric communication has yielded a procedure for locating cryptic binding sites with allosteric communication propensity. Going forward we will exploit these findings to develop a systematic workflow to identify allosteric modulator binding sites. To demonstrate the use of the workflow we will also develop allosteric modulators for gpcrs. Our strong preliminary data shows that this project will lead to a reliable workflow that can be used to identify allosteric modulators for gpcrs. This workflow will also be broadly applicable to other proteins. (3) our studies on trimeric g proteins have shown that disease associated residue mutations allosteric to the nucleotide binding site have a profound effect on the activation mechanism of g proteins. Going forward we propose to dissect the similarities and differences in mechanism of GΒΓ dissociation from GΑ subunit and the effect of mutations on this dissociation process.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $44,500 | |
| Amendment | $400,500 | |
| Amendment | $400,500 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $445,000 |
Quick answers
Who received award R35GM156498?
R35GM156498 was awarded to Beckman Research Institute Of The City Of Hope by National Institute of General Medical Sciences (National Institutes of Health) on February 1, 2025.
How much is award R35GM156498 worth?
$1,290,500 has been obligated on R35GM156498.
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