Four ways of being an agonist: multiple sequence determinants of efficacy at D2 dopamine receptors

Neve, Kim A.; Wiens, Brenda L.

doi:10.1042/bst0230112

Cited by 8 publications

(11 citation statements)

References 3 publications

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“…D2R also contains TM5 serine residues ( Supplementary Fig. 1a ), where mutagenesis studies support that they both contribute to ligand efficacy and overall G protein activation 32 , 33 , and are also essential for aripiprazole recognition 34 .…”

Section: Resultsmentioning

confidence: 98%

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

et al. 2017

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Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy could facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands.

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Section: Resultsmentioning

confidence: 98%

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

et al. 2017

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“…of the receptor's respective putative extracellular loops, especially e 2 and e 3 , and sometime their N-terminal segments. Similarly, wavelet transformation of the hydrophobically transformed amino acid series of the long form, D 2 dopamine receptor suggested leading eigenvector hydrophobic mode locations in the e 2 and e 3 regions (Mandell et al, 2003), extracellular to the transmembrane regions of the putative dopamine binding site (Dal Toso et al, 1989;Kozell et al, 1994;Neve and Wiens, 1995;Woodward et al, 1994). Mode-targeted, eigenvector template-designed peptides demonstrated significant positive modulatory effects on D 2 dopamine receptor-transfected cellular function, as well as dramatically augmenting dopamine-mediated behavior in the rat brain (Mandell et al, 2003).…”

Section: Locating Putative Allosteric Sites By Representing the M 1 Achr's Leading Eigenvector Modes As Modular Densities In The Morlet Wmentioning

confidence: 95%

Designing Human m1 Muscarinic Receptor-Targeted Hydrophobic Eigenmode Matched Peptides as Functional Modulators

Selz

Mandell

Shlesinger

et al. 2004

Biophysical Journal

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A new proprietary de novo peptide design technique generated ten 15-residue peptides targeting and containing the leading nontransmembrane hydrophobic autocorrelation wavelengths, "modes", of the human m(1) muscarinic cholinergic receptor, m(1)AChR. These modes were also shared by the m(4)AChR subtype (but not the m(2), m(3), or m(5) subtypes) and the three-finger snake toxins that pseudoirreversibly bind m(1)AChR. The linear decomposition of the hydrophobically transformed m(1)AChR amino acid sequence yielded ordered eigenvectors of orthogonal hydrophobic variational patterns. The weighted sum of two eigenvectors formed the peptide design template. Amino acids were iteratively assigned to template positions randomly, within hydrophobic groups. One peptide demonstrated significant functional indirect agonist activity, and five produced significant positive allosteric modulation of atropine-reversible, direct-agonist-induced cellular activation in stably m(1)AChR-transfected Chinese hamster ovary cells, reflected in integrated extracellular acidification responses. The peptide positive allosteric ligands produced left-shifts and peptide concentration-response augmentation in integrated extracellular acidification response asymptotic sigmoidal functions and concentration-response behavior in Hill number indices of positive cooperativity. Peptide mode specificity was suggested by negative crossover experiments with human m(2)ACh and D(2) dopamine receptors. Morlet wavelet transformation of the leading eigenvector-derived, m(1)AChR eigenfunctions locates seven hydrophobic transmembrane segments and suggests possible extracellular loop locations for the peptide-receptor mode-matched, modulatory hydrophobic aggregation sites.

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“…Dopamine receptor mutation data. − ,− Data is shown for the consensus binding pocket defined using structure-based generic position numbers from GPCRdb . Wild-type residues for the orthologues involved in mutation studies and the mutant residue are shown (note that only the mutations which have a data point shown in the table were actually carried out, the table is organized for comparability among orthologues).…”

Section: Dopamine Receptor Mutationsmentioning

confidence: 99%

Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

Vass¹,

Podlewska

Esch³

et al. 2018

J. Med. Chem.

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The aminergic family of G protein-coupled receptors (GPCRs) plays an important role in various diseases and represents a major drug discovery target class. Structure determination of all major aminergic subfamilies has enabled structurebased ligand design for these receptors. Site-directed mutagenesis data provides an invaluable complementary source of information for elucidating the structural determinants of binding of different ligand chemotypes. The current study provides a comparative analysis of 6692 mutation data points on 34 aminergic GPCR subtypes, covering the chemical space of 540 unique ligands from mutagenesis experiments and information from experimentally determined structures of 52 distinct aminergic receptor−ligand complexes. The integrated analysis enables detailed investigation of structural receptor−ligand interactions and assessment of the transferability of combined binding mode and mutation data across ligand chemotypes and receptor subtypes. An overview is provided of the possibilities and limitations of using mutation data to guide the design of novel aminergic receptor ligands.

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Four ways of being an agonist: multiple sequence determinants of efficacy at D2 dopamine receptors

Cited by 8 publications

References 3 publications

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

Designing Human m1 Muscarinic Receptor-Targeted Hydrophobic Eigenmode Matched Peptides as Functional Modulators

Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

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