# Structure of Sphingosine 1-phosphate Receptors

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2021 · $66,390

## Abstract

Alan Culbertson Summary NIH F32
Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule whose presence is
required for normal vascular development and endothelial integrity, though acute increases in
S1P concentrations result in cardiac death. S1P binds five G protein coupled receptors (GPCRs;
S1PR1-5), each of which form complexes with various G proteins (Gi, Gq, and G12/13). An array of
genetic models in mice have provided a greater understanding of the S1P signaling pathways.
This knowledge has led the S1P receptors to be the target of various drugs including fingolimod,
the first-line treatment for relapsing multiple sclerosis. In addition, increased production of S1P
leads to stimulation of S1PR1, which leads to activation of the transcription factors NF-κB and
STAT3, leading to numerous types of cancer including breast cancer and lymphomas. Despite
this underlying biological and medical importance, there is little in vitro analysis of these
receptors and structural information is only available for S1PR1 bound to an antagonist in the
inactive conformation. My objective is to determine the high-resolution structure of S1PR1
bound to Gi protein in its functional signaling complex using single-particle cryo-electron
microscopy (cryo-EM). I will then characterize these interactions using mutagenesis and
biophysical techniques such as microscale thermophoresis and surface plasmon resonance. In
addition, I strive to obtain structural information for S1PR1-5 in its apo or ligand bound state by
screening various constructs to make S1PRs larger in mass, allowing for particle alignment during
cryo-EM data processing. These studies will advance the understanding of GPCR-G protein
interactions and enable the engineering of novel drugs that target the S1PRs to treat numerous
diseases or cancer.

## Key facts

- **NIH application ID:** 10091966
- **Project number:** 5F32GM136092-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Alan Thomas Culbertson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091966

## Citation

> US National Institutes of Health, RePORTER application 10091966, Structure of Sphingosine 1-phosphate Receptors (5F32GM136092-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10091966. Licensed CC0.

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