Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor

Arnam, Ethan B. Van; Lester, Henry A.; Dougherty, Dennis A.

doi:10.1021/cb200153g

Cited by 26 publications

(19 citation statements)

References 40 publications

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“…Monte Carlo simulation studies have indicated that in the β2AR, the amino acid residues Cys 285, Trp 286, and Phe 290 (CW × P motif) constitute the aromatic triad and ligand interaction in this region can couple to and modulate the bend angle kink at the Pro 288 leading to receptor activation (Shi et al, 2002). Rotational toggle of conserved residues also activated agonists in histamine H1 receptors (Jongejan et al, 2005), D2 dopamine receptors (Van Arnam, Lester, & Dougherty, 2011), and trace amine-associated receptors (Tan, Groban, Jacobson, & Scanlan, 2008). Several computer modeling studies with the cannabinoid (CB) receptor were reported.…”

Section: Introductionmentioning

confidence: 99%

Advances in Methods to Characterize Ligand-Induced Ionic Lock and Rotamer Toggle Molecular Switch in G Protein-Coupled Receptors

Xie

Chowdhury

2013

G Protein Coupled Receptors - Structure

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Structural biology of GPCRs has made significant progress upon recently developed technologies for GPCRs expression/purification and elucidation of GPCRs crystal structures. The crystal structures provide a snapshot of the receptor structural disposition of GPCRs itself or with cocrystallized ligands, and the results are congruent with biophysical and computer modeling studies reported about GPCRs conformational and dynamics flexibility, regulated activation, and the various stabilizing interactions, such as “molecular switches.” The molecular switches generally constitute the most conserved domains within a particular GPCR superfamily. Often agonist-induced receptor activation proceeds by the disruption of majority of these interactions, while antagonist and inverse agonist act as blockers and structural stabilizers, respectively. Several elegant studies, particularly for the β2AR, have demonstrated the relationship between ligand structure, receptor conformational changes, and corresponding pharmacological outcomes. Thus, it is of great importance to understand GPCRs activation related to cell signaling pathways. Herein, we summarize the steps to produce functional GPCRs, generate suitably fluorescent labeled GPCRs and the procedure to use that to understand if ligand-induced activation can proceed by activation of the GPCRs via ionic lock switch and/or rotamer toggle switch mechanisms. Such understanding of ligand structure and mechanism of receptor activation will provide great insight toward uncovering newer pathways of GPCR activation and aid in structure-based drug design.

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Section: Introductionmentioning

confidence: 99%

Advances in Methods to Characterize Ligand-Induced Ionic Lock and Rotamer Toggle Molecular Switch in G Protein-Coupled Receptors

Xie

Chowdhury

2013

G Protein Coupled Receptors - Structure

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“…This motion describes two inverse rotations of the extra‐ and intra‐cellular parts of the GPCR. (B) A DynDom analysis performed on this motion localizes hinge regions at proximity of highly conserved proline residues known to be important for the receptor activation process [40]. (C) Variations of the Cα:Cα distances for all pairs of residues of the B2AR along either our predicted activation motion (map on the right) or the X‐ray motion (map on the left) confirming that these two motions are significantly different.…”

Section: Resultsmentioning

confidence: 84%

Conformational restriction of G‐proteins Coupled Receptors (GPCRs) upon complexation to G‐proteins: A putative activation mode of GPCRs?

et al. 2013

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GPCRs undergo large conformational changes during their activation. Starting from existing X-ray structures, we used Normal Modes Analyses to study the collective motions of the agonist-bound β2-adrenergic receptor both in its isolated "uncoupled" and G-protein "coupled" conformations. We interestingly observed that the receptor was able to adopt only one major motion in the protein:protein complex. This motion corresponded to an anti-symmetric rotation of both its extra- and intra-cellular parts, with a key role of previously identified highly conserved proline residues. Because this motion was also retrieved when performing NMA on 7 other GPCRs which structures were available, it is strongly suspected to possess a significant biological role, possibly being the "activation mode" of a GPCR when coupled to G-proteins.

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“…A TM Pro might be required for the correct conformation of a bent helix that may be critical for protein function or to increase conformational flexibility of the helix (Fig. 6a) (Van Arnam et al, 2011).…”

Section: B Cui and Othersmentioning

confidence: 99%

Effects of erythromycin on the phenotypic and genotypic biofilm expression in two clinical Staphylococcus capitis subspecies and a functional analysis of Ica proteins in S. capitis

Cui

Smooker

Rouch

et al. 2015

Journal of Medical Microbiology

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The ica operon encoding polysaccharide intercellular adhesion, which facilitates biofilm formation in staphylococci, has been extensively studied in Staphylococcus epidermidis and Staphylococcus aureus. Based on in silico analysis, we suggest the following functional model for Ica proteins in S. capitis. IcaA is responsible for polysaccharide synthesis. IcaA and IcaD complete transferring the growing sugar chain to the cell surface; IcaB is a deacetylase, with the same function as IcaB of S. epidermidis. IcaC mainly modifies the synthesized glucan by acetylation. We also examined the effects of subinhibitory concentrations of erythromycin on phenotypic biofilm expression and transcription of biofilm-related genes, using isolates representing the two subspecies of Staphylococcus capitis and different biofilm and resistance phenotypes. On induction with erythromycin, biofilm density was strongly elevated in two erythromycin-resistant S. capitis, but not in three susceptible isolates. In the representative erythromycin-resistant S. capitis subsp. urealyticus, there were significant upregulations of the icaA gene and its positive regulator sarA on transition to the stationary phase without erythromycin induction. There were also significant increases in the transcription levels of icaA, rsbU and sigB corresponding to a very strong biofilm phenotype in the stationary phase on erythromycin stress. In contrast, the representative erythromycin-susceptible S. capitis subsp. capitis displayed upregulation only of altE on entry into the stationary phase with erythromycin induction, but this change was not associated with enhancement of biofilm production. These findings suggest that the two subspecies of S. capitis adopt different pathogenesis and survival strategies to adapt to a hostile environment.

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Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor

Cited by 26 publications

References 40 publications

Advances in Methods to Characterize Ligand-Induced Ionic Lock and Rotamer Toggle Molecular Switch in G Protein-Coupled Receptors

Advances in Methods to Characterize Ligand-Induced Ionic Lock and Rotamer Toggle Molecular Switch in G Protein-Coupled Receptors

Conformational restriction of G‐proteins Coupled Receptors (GPCRs) upon complexation to G‐proteins: A putative activation mode of GPCRs?

Effects of erythromycin on the phenotypic and genotypic biofilm expression in two clinical Staphylococcus capitis subspecies and a functional analysis of Ica proteins in S. capitis

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