# Molecular Regulation of Cardiovascular 7 TM Receptors

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $784,482

## Abstract

PROJECT SUMMARY/ABSTRACT
MOLECULAR REGULATION OF CARDIOVASCULAR SEVEN TRANSMEMBRANE RECEPTORS. All
aspects of cardiovascular function are regulated by receptors of the seven transmembrane receptor (7TMR or
GPCR) family, and they are the commonest target of therapeutic drugs. A universal mechanism regulating
these receptors is desensitization of heterotrimeric G protein signaling. Classically, this is mediated by a two-
step process in which activated receptors are phosphorylated by G protein-coupled receptor kinases, leading
to the binding of a β-arrestin (βarr) molecule which sterically interdicts further activation of the G protein. More
recently it has become clear that βarrs can also serve as multifunctional adaptors which act as signal
transducers in their own right. Moreover, for many receptors ligands can be found which disproportionately
activate either G protein- or βarr-mediated signaling—i.e., "biased ligands" which may possess greater
specificity of action and fewer side effects. Several such drugs, including one for decompensated congestive
heart failure which targets the angiotensin II type 1 receptor (AT1R), have reached clinical trials. Accordingly,
this proposal has three closely linked aims which involve developing a molecular- and atomic-level
understanding of how such βarr-mediated signaling is generated using as model systems two receptors of
great cardiovascular significance, the β2-adrenergic receptor (β2AR) and the AT1R. These aims are: 1) To
discover novel allosteric stabilizers (nanobodies and small molecules) for biased conformations of the AT1R
and β2AR. 2) To delineate the structural basis for biased conformations of the AT1R by X-ray crystallography
and DEER. 3) To determine the structure of GPCR-βarr complexes by cryo-electron microscopy. The insights
which we will generate have the potential to guide the design of powerful new cardiovascular drugs and will
further our understanding of the conserved signaling mechanisms of the greater GPCR family.

## Key facts

- **NIH application ID:** 10199770
- **Project number:** 5R01HL016037-49
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** ROBERT J LEFKOWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $784,482
- **Award type:** 5
- **Project period:** 1976-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199770

## Citation

> US National Institutes of Health, RePORTER application 10199770, Molecular Regulation of Cardiovascular 7 TM Receptors (5R01HL016037-49). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10199770. Licensed CC0.

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