Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function

Kristiansen, Kurt

doi:10.1016/j.pharmthera.2004.05.002

Cited by 526 publications

(410 citation statements)

References 356 publications

Supporting

Mentioning

388

Contrasting

Unclassified

Order By: Relevance

“…Future work may seek to combine the analyses we have accomplished here with syntenic or molecular clock approaches to elucidate receptors' origin and precise evolutionary trajectories. Moreover, our curated MSA should prove useful in increasing accuracy in homology modeling and/or pharmaceutical development for these clincally important receptors (Kristiansen, 2004;Ishiguro, 2004;Evers et al, 2005;Mason et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…We expect that these data will prove extremely useful for studying both the broad patterns governing biogenic amine receptor sequence evolution and the evolutionary trends specific to certain receptor subtypes. Further, our curated MSA should serve as a helpful resource in the ongoing development of homology models and pharmaceutical therapeutics targeting these receptors (Kristiansen, 2004;Ishiguro, 2004;Evers et al, 2005;Mason et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Spielman

Kumar

Wilke

2014

Preprint

View full text Add to dashboard Cite

Biogenic amine receptors play critical roles in regulating behavior and physiology, particularly within the central nervous system, in both vertebrates and invertebrates. These receptors belong to the G-protein coupled receptor (GPCR) family and interact with endogenous bioamine ligands, such as dopamine, serotonin, and epinephrine, and they are targeted by a wide array of pharmaceuticals. Despite these receptors' clear clinical and biological importance, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality, structurally-curated sequence alignment of vertebrate biogenic amine receptors. We demonstrate that aligning GPCR sequences without considering structure produces an alignment with substantial error, whereas a structurally-aware approach greatly improves alignment accuracy. Moreover, we show that phylogenetic inference with our structurally-curated alignment offers dramatic improvements over a structurally-naive alignment. Using the structural alignment and its corresponding phylogeny, we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Spielman

Kumar

Wilke

2014

Preprint

View full text Add to dashboard Cite

show abstract

“…In general, GPCR subfamilies have similar ligands and binding motifs (30). For example, although sphingosine-1-phosphate is able to activate several receptors, these belong to the same rhodopsin-like GPCR subfamily (31,32).…”

Section: Discussionmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide 27 Is a Functional Ligand for Formyl Peptide Receptor-Like 1

Kim

Lee

Kim

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Although the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in the regulation of several immune responses, its target receptors and signaling mechanisms have yet to be fully elucidated in immune cells. In this study, we found that PACAP27, but not PACAP38, specifically stimulated intracellular calcium mobilization and ERK phosphorylation in human neutrophils. Moreover, formyl peptide receptor-like 1 (FPRL1) was identified as a PACAP27 receptor, and PACAP27 was found to selectively stimulate intracellular calcium increase in FPRL1-transfected rat basophile leukocytes-2H3 cell lines. In addition, PACAP27-induced calcium increase and ERK phosphorylation were specifically inhibited by an FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), thus supporting the notion that PACAP27 acts on FPRL1. In terms of the functional role of PACAP27, we found that the peptide stimulated CD11b surface up-regulation and neutrophil chemotactic migration, and that these responses were completely inhibited by WRW4. The interaction between PACAP27 and FPRL1 was analyzed further using truncated PACAPs and chimeric PACAPs using vasoactive intestinal peptide, and the C-terminal region of PACAP27 was found to perform a vital function in the activation of FPRL1. Taken together, our study suggests that PACAP27 activates phagocytes via FPRL1 activation, and that this results in proinflammatory behavior, involving chemotaxis and the up-regulation of CD11b.

show abstract

“…G protein-coupled receptors (GPCRs), the largest family of membrane proteins, are integral parts of interaction networks, which have crucial roles in cellular homeostasis 1 . Glycoprotein hormone receptors (GpHrs) constitute a subfamily of rhodopsin-like GPCRs responsible for signal transduction by thyrotropin (TSH), lutropin or chorionic gonadotropin (LH/CG), and follitropin (FSH) 2,3 .…”

mentioning

confidence: 99%

Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

et al. 2012

View full text Add to dashboard Cite

Glycoprotein hormone receptors show strong negative cooperativity. As a consequence, at physiological hormone concentrations, a single agonist binds to a receptor dimer. Here we present evidence that constitutively active receptors lose cooperative allosteric regulation in direct relation with their basal activity. The most constitutive mutants lost nearly all cooperativity and showed an increase of initial tracer binding, reflecting the ability of each protomer to bind with equal affinity. Allosteric interaction between the protomers takes place at the transmembrane domain. The allosteric message resulting from hormone binding to the ectodomain of one protomer travels 'downward' to its transmembrane domain, before affecting the transmembrane domain of the other protomer. This results in transmission of an 'upward' message lowering the binding affinity of the ectodomain of the second protomer. our results demonstrate a direct relation between the conformational changes associated with activation of the transmembrane domain and the allosteric behaviour of glycoprotein hormone receptors dimers.

show abstract

Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function

Cited by 526 publications

References 356 publications

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Pituitary Adenylate Cyclase-Activating Polypeptide 27 Is a Functional Ligand for Formyl Peptide Receptor-Like 1

Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

Contact Info

Product

Resources

About