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Precise druggability of the PTH type 1 receptor

Vilardaga, Jean-Pierre (2021) Precise druggability of the PTH type 1 receptor. [Dataset] (Submitted)

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Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within the transmembrane domain limits the identification and development of non-peptide small molecule ligands. Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination of molecular dynamics simulations and elastic network model-based methods, we demonstrate that PTHR druggability can be effectively addressed. Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this ensemble of PTHR conformers to identify selective small molecules with strong negative allosteric and biased properties for PTHR signaling in cell and PTH actions in vivo. This study provides a computational pipeline to detect precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs to expedite discoveries of small molecules as novel therapeutic candidates.


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Item Type: Dataset
Status: Submitted
CreatorsEmailPitt UsernameORCID
Vilardaga, Jean-Pierrejpv@pitt.edujpv
ContributionContributors NameEmailPitt UsernameORCID
AuthorSutkeviciute, Ievaies4@pitt.eduUNSPECIFIEDUNSPECIFIED
AuthorPena, Karinakapena@pitt.edukapenaUNSPECIFIED
Date: 14 October 2021
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Type of Data: Mixed
Copyright Holders: JP Vilardaga
Date Deposited: 18 Oct 2021 14:12
Last Modified: 18 Oct 2021 14:12


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