# Structure, Mechanism, and Regulation of PACAP/VIP GPCR subtypes

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $1

## Abstract

Among the pharmacologically important Class B G protein-coupled receptors (GPCRs), the PAC1/VPAC
receptors (ADCYAP1R1/VIPR1/VIPR2) for pituitary adenylate cyclase activated polypeptide (PACAP,
ADCYAP1) and vasoactive intestinal peptide (VIP) have been implicated in several disorders, including chronic
pain and stress-related behavioral abnormalities which are among the most prevalent global neurological
challenges today. However, the development of reagents targeting these receptors for potential therapeutics
has been hampered by the lack of full-length PAC1/VPAC receptor structural information, and mechanistic
understandings of how ligand binding can differentially drive conformational changes for receptor activation
and biased signaling. Accordingly, the overarching aim of this proposal is to employ state-of-the-art
computational methods to model PAC1/VPAC receptor structure and dynamics, with the goal of developing
small-molecule compounds to modulate their functions. For each receptor subtype, the identification of unique
structural features that allow for specific ligand interactions and transducer protein associations will facilitate
the rational design and optimization of small-molecule ligands. Towards that goal, three specific aims will be
pursued: (1) to model and compare structures and mechanisms that determine neuropeptide selectivity and
function among the physiologically relevant PAC1Null, PAC1Hop1, VPAC1, and VPAC2 receptor subtypes; (2)
to delineate PAC1/VPAC receptor-transducer protein interactions and specificity; and (3) to develop and
optimize small molecules for selective PAC1 and VPAC receptor regulation. Our preliminary data have
established the modeling methodology with the PAC1Null receptor, demonstrated distinct signaling behaviors
of the PAC1/VPAC receptors, and identified two different PAC1Null antagonists. Under Aims 1 and 2, we will
use homology modeling, protein structure refinement, and molecular dynamics simulations to study the
receptors that are ligand-free and complexed with a neuropeptide (PACAP/VIP) or a transducer protein
(Gs/Gq/β-arrestins). In particular, we will elucidate the binding sites that are key for ligand specificity as well as
conformational states that facilitate long-term signaling. Receptor mutagenesis and constructs will inform
and/or substantiate the receptor models. Under Aim 3, we will integrate molecular docking and simulations,
organic synthesis, and molecular and cellular assays to develop selective small-molecule modulators.
Especially, the strategies to target the orthosteric and allosteric sites will be tested. Our multidisciplinary
approach is innovative as it provides an unparalleled and comprehensive means to investigate the
PAC1/VPAC receptors in various conditions and functional states. Further, the proposed research is
significant, because it will close fundamental gaps in understanding how molecular structures and dynamics
can dictate PAC1/VPAC receptor mechanisms. Finally, gi...

## Key facts

- **NIH application ID:** 10473545
- **Project number:** 5R01GM129431-05
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Jianing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473545

## Citation

> US National Institutes of Health, RePORTER application 10473545, Structure, Mechanism, and Regulation of PACAP/VIP GPCR subtypes (5R01GM129431-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10473545. Licensed CC0.

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