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Precision druggability of a class B GPCR, the PTH type 1 receptor
Author(s) -
Sutkeviciute Ieva,
Lee JiYoung,
White Alex,
Doruker Pemra,
Peña Karina,
Sanker Subramaniam,
Lei Saifei,
Kaynak Burak,
Chang Wenhan,
Bahar Ivet,
Vilardaga JeanPierre
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03186
Subject(s) - druggability , g protein coupled receptor , allosteric regulation , computational biology , small molecule , receptor , chemistry , biology , biochemistry , gene
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 nonpeptide 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 in PTHR signaling that could be extended broadly to GPCRs, in particular to class B peptide hormone receptors to expedite discoveries of small molecules toward the treatment of diverse hormonal and metabolic diseases.