Basal Histamine H<sub>4</sub> Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif

Wifling, David; Pfleger, Christopher; Kaindl, Jonas; Ibrahim, Passainte; Kling, Ralf C.; Buschauer, Armin; Gohlke, Holger; Clark, Timothy

doi:10.1002/chem.201902801

Cited by 10 publications

(13 citation statements)

References 77 publications

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“…We combined extensive MD simulations in combination with a rigidity theory-based free energy perturbation approach to scrutinize the role of dynamic, i.e., entropically dominated, allostery for cooperativity within and between the CL-CNBDs of the subunits, study signal transmission evoked by bound cAMP, and identify interactions involved in the signaling. The rigidity theory-based free energy perturbation approach (20) proved successful in related studies of membrane proteins (40)(41)(42). Our results allowed us to map out distinct routes within the tetrameric CL-CNBD that modulate different cAMP binding responses in HCN2 channels through disjunct salt bridge interactions.…”

Section: Discussionmentioning

confidence: 88%

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Pfleger

Kusch

Kondapuram

et al. 2020

Preprint

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30Opening of hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels 31 is controlled by membrane hyperpolarization and binding of cyclic nucleotides to the 32 tetrameric cyclic nucleotide-binding domain (CNBD), attached to the C-linker disk (CL). 33Confocal patch-clamp fluorometry revealed a pronounced cooperativity of ligand binding 34 among protomers. However, by which pathways allosteric signal transmission occurs 35 remained elusive. Here, we investigate how changes in the structural dynamics of the CL-36CNBD of mouse HCN2 upon cAMP binding relate to inter-and intrasubunit signal 37transmission. Applying a rigidity theory-based approach, we identify two intersubunit 38and one intrasubunit pathways that differ in allosteric coupling strength between cAMP 39 binding sites or towards the CL. These predictions agree with results from 40 electrophysiological and patch-clamp fluorometry experiments. Our results map out 41 distinct routes within the CL-CNBD that modulate different cAMP binding responses in 42HCN2 channels. They signify that functionally relevant submodules may exist within and 43 across structurally discernable subunits in HCN channels.

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Section: Discussionmentioning

confidence: 88%

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Pfleger

Kusch

Kondapuram

et al. 2020

Preprint

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“…This also includes structural water molecules, metal ions, and cofactors, which can be considered in the analysis. Finally, CNA has been used to understand signal propagation [54] and allosteric effects [55] , [56] within biomolecules, primarily within membrane proteins, expanding the application scope of CNA.…”

Section: Resultsmentioning

confidence: 99%

Can constraint network analysis guide the identification phase of KnowVolution? A case study on improved thermostability of an endo-β-glucanase

Contreras

Nutschel

Beust

et al. 2021

Computational and Structural Biotechnology Journal

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“…4A). A recent study indeed reported roles of ECL2 in modulating class A GPCR basal activity 29 . Fig.…”

Section: Fig 3 In Vitro Basal Activities (A)mentioning

confidence: 94%

Functions of olfactory receptors are decoded from their sequence

Cong

Ren

Pacalon

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diversified. This work investigated how the functional variations in olfactory GPCRs (ORs)−the largest GPCR family−are encoded in the primary sequence. With the aid of site-directed mutagenesis and molecular simulations, we built machine learning models to predict OR-ligand pairs as well as basal activity of ORs. In vitro functional assay confirmed 20 new OR-odorant pairs, including 9 orphan ORs. Residues around the odorant-binding pocket dictate the odorant selectivity/specificity of the ORs. Residues that encode the varied basal activities of the ORs were found to mostly surround the conserved motifs as well as the binding pocket. The machine learning approach, which is readily applicable to mammalian OR families, will accelerate OR-odorant mapping and the decoding of combinatorial OR codes for odors. IntroductionFunctions of proteins are encoded within either diversified or conserved subparts of their sequence. G protein-coupled receptors (GPCRs) are the most remarkable examples of this phenomenon. GPCRs are the largest membrane protein family and the targets of about 40% of marketed drugs 1 . The human genome contains over 800 genes coding for GPCRs, which exert differentiated and specific functions in the complex cellular signaling network. Half of these genes are olfactory receptors (ORs), which endow us with fascinating capacities of odor discrimination 2,3 . Mammalian GPCRs conserve a typical structural architecture of seven transmembrane helices (7TM) that house an orthosteric ligand-binding pocket 4 . Their intrinsic signaling mechanism, large-scale conformational changes to accommodate their cognate G proteins, is encoded in conserved motifs throughout the 7TM, which form a network of inter-TM contacts converging to their cytoplasmic part 5 . Namely, the "D(E)RY", "CWLP" and "NPxxY" motifs in TM3, TM6 and TM7, respectively, are the most conserved hubs of the allosteric communication between the orthosteric pocket and the cytoplasmic side of class A GPCRs 4 . The rest of the GPCR sequences, especially the ligand-binding pocket, have diversified extensively, which resulted in huge variations in the receptors' function. Amongst the hundreds of variable residues in the GPCR sequences, it is very likely that some are specialized for the receptors' ligand specificity/selectivity while, others encode more information on the receptors' intrinsic activity.This study focused on the divergence of ligand-dependent and ligand-independent (or basal) activities of olfactory class A GPCRs. We seek to identify amino acid positions that are critical for the receptors' functional heterogeneity. ORs discriminate a vast spectrum of volatile molecules (odorants) and code for an innumerous number of odors perceived in the brain. The manyto-many relationships between ORs and odorants are key to understanding odor perception 6 . ORs are also expressed ectopically, some of which have ...

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Basal Histamine H₄ Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif

Cited by 10 publications

References 77 publications

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Can constraint network analysis guide the identification phase of KnowVolution? A case study on improved thermostability of an endo-β-glucanase

Functions of olfactory receptors are decoded from their sequence

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Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif

Cited by 10 publications

References 77 publications

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Pathways of inter- and intrasubunit allosteric signaling in the C-linker disk and cyclic nucleotide-binding domain of HCN2 channels

Can constraint network analysis guide the identification phase of KnowVolution? A case study on improved thermostability of an endo-β-glucanase

Functions of olfactory receptors are decoded from their sequence

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Basal Histamine H₄ Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif