Engineering a GPCR−Ligand Pair That Simulates the Activation of D2L by Dopamine

Tschammer, Nuška; Dörfler, Miriam; Hübner, Harald; Gmeiner, Peter

doi:10.1021/cn900001b

Cited by 27 publications

(47 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(6) For binding Dopamine, the following residues were considered as interacting residues: 3.32ASP, 5.42SER, 5.43SER, 5.46SER, 6.48TRP, 6.51PHE, 6.52PHE and 6.55HIS according to Floresca et al (6). Additionally, these residues were considered also in others studies involving molecular docking, but in a different constellation, concluding that they are important for general ligand binding to the D2R (26,28,29). To compare the performance between the endogenous ligand, the selective D2R/D3R-agonist Quinpirole and the selective D2R-antagonist Raclopride, an additional conserved residue, 7.43TYR, was considered as part of the flexible residues in the docking procedure, since some ligands, especially antagonists, are believed to access a Secondary Binding Pocket (SBP) (30,31).…”

Section: Resultsmentioning

confidence: 99%

Creating a valid in silico Dopamine D2-receptor model for small molecular docking studies

Bueschbell

Preto

Barreto

et al. 2017

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd Edition

View full text Add to dashboard Cite

Due to the clinical importance of the Dopamine D2-receptor (D2R) in several brain dysfunctions, the utilization of in silico models for drug development is a growing field of investigation. We provided a transparent and reproducible pipeline for creating a valid D2R model for small molecular docking studies. Furthermore, we suggested a binding pocket for the endogenous ligand of D2R, which was attained upon careful consideration of the available experimental data. Molecular docking studies with Dopamine, Quinpirole and Raclopride allowed also a better understanding of the binding pocket characteristics.

show abstract

Section: Resultsmentioning

confidence: 99%

Creating a valid in silico Dopamine D2-receptor model for small molecular docking studies

Bueschbell

Preto

Barreto

et al. 2017

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd Edition

View full text Add to dashboard Cite

show abstract

“…6.52 W (Tschammer et al, 2010). The mutation of His393 6.55 , which is conserved within the D 2 -like dopamine receptors, led to an increase in the affinity of 1,4-disubstituted phenylpiperazines to the H393 6.55 A receptor (Ehrlich et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D_2LReceptor

et al. 2010

Self Cite

View full text Add to dashboard Cite

In our previous studies, we demonstrated that the mutation of His393 6.55 to alanine results in an increased affinity of 1,4-disubstituted phenylpiperazines to the dopamine D 2L receptor. This change most likely accounts for the reduced steric hindrance in this part of the binding pocket. In this work, we investigated the role of the steric hindrance imposed by the residue His393 6.55 for the receptor activation modulated by 1,4-disubstituted aromatic piperidines/piperazines. Site-directed mutagenesis and ligand modifications were used to probe the structural basis of ligand efficacy. The operational model of agonism was used to quantify the ligand bias between the ability of compounds to inhibit cAMP accumulation and stimulate extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas substantial ligand-biased signaling was observed for the D 2L wild-type receptor, an overall increase in agonism was observed for the D 2L H3936.55 A mutant without noteworthy functional selectivity. Targeted chemical modification of the phenylpiperazine moiety at the site of its interaction with the residue His393 6.55 led to the functionally selective ligand {3-[4-(2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-propyl}-pyrazol[1,5-a]pyridine-3-carboxamide (FAUC350) that has distinct signaling profiles toward adenylyl cyclase and ERK1/2. FAUC350 behaves as an antagonist in the inhibition of cAMP accumulation and as a partial agonist in the stimulation of ERK1/2 phosphorylation (efficacy ϭ 55%). Overall, the residue His393 6.55 and proximate molecular substructures of receptor ligands were identified to be crucial for multidimensional ligand efficacy.

show abstract

“…Inhibition of cAMP accumulation assay and phosphoERK1/2 ELISA assay were performed as previously described. 45 A detailed description is available in the Supporting Information.…”

Section: Saturation Experimentsmentioning

confidence: 99%

Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics

Koschatzky

Tschammer

Gmeiner

2011

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

T he ability to form spatial complexes allowing molecular interactions between receptor protomers facilitates cooperative effects and tissue specific control of neuronal activity. Thus, heterodimerization is discussed as an integral feature of G-protein coupled receptor (GPCR) mediated signal transduction. 1À3 Intramembrane receptorÀreceptor interactions of associated protomers may modify binding and activating properties of GPCR ligands. 4À7 Using F€ orster resonance energy transfer (FRET) technique, a recent study on the interactions between R 2A -adrenergic and μ-opioid receptors demonstrated a transinhibitory effect between the protomers. In detail, morphine binding to the μ-opioid receptor triggered the conformational changes in the norepinephrine-occupied R 2A -adrenergic receptor leading to the inhibition of its signaling. 8 Physical interactions between δ-and μ-opioid receptors were suggested to modulate μ-mediated tolerance and dependence 9 when the development of bivalent ligands was constituted as a useful approach to investigate changes in receptor properties as a consequence to dimerization. 10,11 Heterodimerization is also a highly relevant phenomenon for dopamine receptor mediated signaling. 12,13 Demonstrating the development of a new complex with enhanced functional activity through hetero-oligomerization, the physical interaction between the dopamine D 2L and the somatostatin SST5 receptor was investigated via radioligand binding studies, functional assays, and FRET microscopy. 14 The heterooligomerization of D 2L and SST5, known for their colocalization in the central nervous system (CNS), led to a synergistic effect on binding and signaling as molecular cross-talk and the correlation between activated receptor function and oligomerization was stressed.Dopaminergic systems have been also described to functionally interact with the neuromodulatory peptide neurotensin (NT, pE-L-Y-E-N-K-P-R-R-P-Y-I-L) 15 which is suggested to play a role in the pathophysiology of brain diseases including schizophrenia, Parkinson's disease. and Morbus Alzheimer. 16À18 Thus, neurotensin was shown to negatively alter binding affinity of the dopamine receptor agonist [ 3 H]N-n-propyl-nor-apomorphine in specific brain areas. 19À25 However, biomolecular interactions and a putative heteromer formation between dopamine receptors and neurotensin receptors have not been investigated yet.Employing fluorescence detected coimmunoprecipitation and radioligand binding experiments, we herein demonstrate that coexpression of dopamine D 2L receptor and the neurotensin receptor subtype NTS 1 in human embryonic kidney cells (HEK293 cells) leads to physical interaction at a molecular level. In this in vitro system, a trans-inhibitory effect on the agonist binding affinity of D 2 was observed in the presence of neurotensin. A biochemical fingerprint 26 of the D 2L -NTS 1 heteromer was explored by investigating the effect of both neurotensin and NTS 1 on the D 2 receptor binding properties of different ABSTRACT: Dopaminergic systems ...

show abstract

Engineering a GPCR−Ligand Pair That Simulates the Activation of D_2L by Dopamine

Cited by 27 publications

References 58 publications

<strong>Creating a valid <em>in silico</em> Dopamine D2-receptor model for small molecular docking studies</strong>

<strong>Creating a valid <em>in silico</em> Dopamine D2-receptor model for small molecular docking studies</strong>

Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D_2LReceptor

Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics

Contact Info

Product

Resources

About

Engineering a GPCR−Ligand Pair That Simulates the Activation of D2L by Dopamine

Cited by 27 publications

References 58 publications

<strong>Creating a valid <em>in silico</em> Dopamine D2-receptor model for small molecular docking studies</strong>

<strong>Creating a valid <em>in silico</em> Dopamine D2-receptor model for small molecular docking studies</strong>

Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D2LReceptor

Cross-Receptor Interactions between Dopamine D2L and Neurotensin NTS1 Receptors Modulate Binding Affinities of Dopaminergics

Contact Info

Product

Resources

About

Engineering a GPCR−Ligand Pair That Simulates the Activation of D_2L by Dopamine

Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D_2LReceptor

Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics