# Molecular basis of activation of the prototypic class B G protein-coupled secretin receptor

> **NIH NIH R01** · MAYO CLINIC ARIZONA · 2020 · $372,298

## Abstract

PROJECT SUMMARY/ABSTRACT
Our OVERALL OBJECTIVE is to elucidate the molecular basis of activation of class B GPCRs, using the
prototypic secretin receptor (SecR) as a model. Insights will fill key gaps in knowledge and facilitate ultimate
development of drugs exhibiting various activity profiles. Class B GPCRs include established targets for
treatment of diabetes, obesity, osteoporosis, migraine, anxiety, and depression. However, therapeutics remain
suboptimal, and the receptor class has been refractory to development of small molecule, orally active drugs,
at least in part, due to lack of understanding of the structure and functional dynamics required for receptor
activation. We now have novel, unique insights into both of these, including high-resolution structures of
related, full-length, G protein-coupled holoreceptors, that highlight the importance of the interface between the
receptor N-terminal extracellular domain (ECD) and the transmembane domain core in ligand binding and
receptor activation. Component aims are directed toward understanding the conformational dynamics of this
interface for agonist binding and receptor activation, and using our breakthroughs in use of single particle cryo-
EM to provide a structural framework for this work. Aim 1, elucidates molecular events involved in secretin
peptide engagement with its receptor core, and key determinants for its activity, testing the hypothesis that
orientation (and interaction) of ECD and core domains plays a critical role in directing and positioning the
orthosteric agonist pharmacophore near its site of action. We will explore this locus using cysteine trapping to
compare spatial approximations for analogous inactive and active probes, applied to wild type receptor, as well
as dimerization-deficient receptor constructs. Rational structure-activity analysis for binding and a broad range
of biological activities of the agonist pharmacophore will also be performed, with results used to provide
insights into determinants of activation and effector specificity. Aim 2, investigates the relative orientations and
interactions between SecR ECD and core, exploring functional implications of this interrelationship, testing the
hypothesis that these domains can interact in various ways that affect states of quiescence and activation. This
will be approached by receptor mutagenesis to modify domain interactions, establishment of domain-domain
disulfide bonds by incorporating cysteines at the top of the receptor core and bottom of the ECD, as well as
using immunologic probes of predicted surfaces of the receptor amino terminus to determine access and to be
used in resonance transfer techniques. Aim 3, elucidates SecR inactive and active/holostructure using single
particle cryo-EM, testing the hypothesis that mapping of biochemical and functional data onto high resolution
3D structures, including agonist-receptor-heterotrimeric G protein and inactive antagonist-occupied receptor,
will help to elu...

## Key facts

- **NIH application ID:** 10003345
- **Project number:** 5R01GM132095-02
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** LAURENCE J MILLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,298
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003345

## Citation

> US National Institutes of Health, RePORTER application 10003345, Molecular basis of activation of the prototypic class B G protein-coupled secretin receptor (5R01GM132095-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003345. Licensed CC0.

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