Precise druggability of the PTH type 1 receptor

Sutkevičiūtė, Ieva; Lee, Ji Young; White, Anna Marie; Maria, Christian Santa; Peña, Karina A.; Savransky, Sofya; Doruker, Pemra; Li, Hongchun; Lei, Saifei; Kaynak, Burak; Tu, Chia-Ling; Clark, Lisa J.; Sanker, Subramaniam; Gardella, Thomas J.; Chang, Wenhan; Bahar, İvet; Vilardaga, Jean-Pierre

doi:10.1038/s41589-021-00929-w

Cited by 16 publications

(4 citation statements)

References 49 publications

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“…Furthermore, as shown in Figure , the outer region of transmembrane helices primarily includes three binding regions: (1) TM1/2/3 extracellular region, which is present in various states and contains binding sites for LSN3160440 [positive allosteric modulators (PAM)] and TT-OAD2 (PAM) and previously studied small-molecule Pitt12 (NAM); , (2) the middle region of TM6, which includes analytically regulated NAMs of class B1 GPCRs (such as PF06372222, NNC0640, MK0893, and CP376395); ,,− (3) the cytoplasmic region of TM6, predicted only in the active state, with a reported binding site for compound 2 (PAM) . Moreover, CavityPlus and DoGSiteScorer also focused on predicting potential binding sites in proteins and providing information about their features, shape, and location.…”

Section: Resultsmentioning

confidence: 99%

Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models

Li,

Zhang,

et al. 2024

ACS Chem. Neurosci.

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Parathyroid hormone (PTH) type 1 receptor (PTH1R), as a typical class B1 G protein-coupled receptor (GPCR), is responsible for regulating bone turnover and maintaining calcium homeostasis, and its dysregulation has been implicated in the development of several diseases. The extracellular domain (ECD) of PTH1R is crucial for the recognition and binding of ligands, and the receptor may exhibit an autoinhibited state with the closure of the ECD in the absence of ligands. However, the correlation between ECD conformations and PTH1R activation remains unclear. Thus, this study combines enhanced sampling molecular dynamics (MD) simulations and Markov state models (MSMs) to reveal the possible relevance between the ECD conformations and the activation of PTH1R. First, 22 intermediate structures are generated from the autoinhibited state to the active state and conducted for 10 independent 200 ns simulations each. Then, the MSM is constructed based on the cumulative 44 μs simulations with six identified microstates. Finally, the potential interplay between ECD conformational changes and PTH1R activation as well as cryptic allosteric pockets in the intermediate states during receptor activation is revealed. Overall, our findings reveal that the activation of PTH1R has a specific correlation with ECD conformational changes and provide essential insights for GPCR biology and developing novel allosteric modulators targeting cryptic sites.

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Section: Resultsmentioning

confidence: 99%

Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models

Li,

Zhang,

et al. 2024

ACS Chem. Neurosci.

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“…PROPKA , was used to predict the expected protonation state of all residues at pH 7.0. MD simulation systems were built via the CHARMM-GUI server − with the CHARMM36 force field. , Parameters for ligand were obtained with the CGenFF using RESP2 partial charges . The receptor was oriented according to the Orientations of Proteins in Membranes (OPM) database and inserted into a homogeneous membrane composed of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC) in a box with a size of approximately 7.9 nm × 7.9 nm × 12.7 nm .…”

Section: Methodsmentioning

confidence: 99%

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

Yang

Lin

Xia

et al. 2022

J. Chem. Inf. Model.

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The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R.

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“…The parathyroid hormone receptor (PTH1R), a class B1 GPCR, 327 is by parathyroid hormone and parathyroid hormone-related peptides and plays a central role in maintaining mineral ion homeostasis and skeletal metabolism. [328][329][330] Recently, a highly selective PTH1R agonist, the orally active non-peptidic small molecule PCO371 (54) (Fig. 28), was identified and is currently undergoing phase 1 clinical trials to treat hypoparathyroidism.…”

Section: Fig 14 Two-dimensional (2d) Chemical Structures Of Synthetic...mentioning

confidence: 99%

G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery

Zhang,

Chen,

et al. 2024

Sig Transduct Target Ther

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G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class of drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects or allosteric effects, and biased signaling or balanced signaling, characterize the complexity of GPCR dynamic features. In this study, we first review the structural advancements, activation mechanisms, and functional diversity of GPCRs. We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years. Particularly, an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms. Finally, we highlight how the widespread GPCR-druggable allosteric sites can guide structure- or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

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Precise druggability of the PTH type 1 receptor

Cited by 16 publications

References 49 publications

Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models

Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery

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