Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 23

Publication Record

Connections

Structural basis of ligand binding modes at the neuropeptide Y Y receptor.
Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B
(2018) Nature 556: 520-524
MeSH Terms: Arginine, Binding Sites, Crystallography, X-Ray, Dihydropyridines, Diphenylacetic Acids, Humans, Inositol Phosphates, Ligands, Molecular Docking Simulation, Mutant Proteins, Mutation, Neuropeptide Y, Nuclear Magnetic Resonance, Biomolecular, Phenylurea Compounds, Protein Binding, Receptors, Neuropeptide Y, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added March 21, 2020
Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) . A number of peptides and small-molecule compounds have been characterized as YR antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human YR bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of YR to several structurally diverse antagonists and the determinants of ligand selectivity. The YR structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into YR can enable structure-based drug discovery that targets NPY receptors.
0 Communities
1 Members
0 Resources
MeSH Terms
G Protein Preassembly Rescues Efficacy of W Toggle Mutations in Neuropeptide Y Receptor.
Kaiser A, Hempel C, Wanka L, Schubert M, Hamm HE, Beck-Sickinger AG
(2018) Mol Pharmacol 93: 387-401
MeSH Terms: Amino Acid Sequence, Binding Sites, Dose-Response Relationship, Drug, GTP-Binding Proteins, HEK293 Cells, Humans, Mutation, Neuropeptide Y, Protein Structure, Secondary, Receptors, Neuropeptide Y
Show Abstract · Added March 24, 2020
Ligand binding and pathway-specific activation of G protein-coupled receptors is currently being studied with great effort. Individual answers may depend on the nature of the ligands and the effector pathway. Recently, we have presented a detailed model of neuropeptide Y bound to the YR. Accordingly, the C-terminal part of the peptide binds deeply in the transmembrane bundle and brings the side chain of the most essential Y in close proximity to W Here, we investigate the role of this interaction for ligand binding and activation of this receptor. BRET sensors were used for detailed investigation of effector coupling and led to the identification of preassembly of the YR-G complex. It further confirmed ligand-dependent recruitment of arrestin3. Using equally sensitive readouts for G activation and arrestin recruitment as well as quantification with operational models of agonism allowed us to identify a strong inherent bias for G activation over arrestin3 recruitment for the wild-type receptor. By systematic mutagenesis, we found that W does not contribute to the binding affinity, but acts as an allosteric connector to couple ligand binding to G activation and arrestin3 recruitment. However, even mutagenesis to a small threonine did not lead to a complete loss of signaling. Interestingly, signaling was restored to wild-type levels by ligands that contain a naphthylalanine as the C-terminal residue instead of Y Steric and polar contributions of W for the activation of the receptor are discussed in the context of different mechanisms of G protein coupling and arrestin recruitment.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
0 Communities
1 Members
0 Resources
MeSH Terms
Identification and Characterization of the First Selective Y Receptor Positive Allosteric Modulator.
Schubert M, Stichel J, Du Y, Tough IR, Sliwoski G, Meiler J, Cox HM, Weaver CD, Beck-Sickinger AG
(2017) J Med Chem 60: 7605-7612
MeSH Terms: Allosteric Regulation, Animals, Arrestins, COS Cells, Chlorocebus aethiops, Cyclohexanols, GTP-Binding Proteins, HEK293 Cells, Humans, Models, Molecular, Receptors, Neuropeptide Y, Signal Transduction
Show Abstract · Added March 17, 2018
The human Y receptor (YR) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy expenditure, satiety, and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC (tert-butylphenoxycyclohexanol), a novel and selective YR positive allosteric modulator that potentiates YR activation in G-protein signaling and arrestin3 recruitment experiments. The compound has no effect on the binding of the orthosteric ligands, implying its allosteric mode of action at the YR and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate YR agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native YR, demonstrating YR positive allosteric modulation in vitro.
0 Communities
2 Members
0 Resources
12 MeSH Terms
A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y R Antagonists.
Burkert K, Zellmann T, Meier R, Kaiser A, Stichel J, Meiler J, Mittapalli GK, Roberts E, Beck-Sickinger AG
(2017) ChemMedChem 12: 75-85
MeSH Terms: Animals, Arginine, Benzazepines, Binding Sites, COS Cells, Cells, Cultured, Chlorocebus aethiops, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation, Molecular Structure, Receptors, Neuropeptide Y, Structure-Activity Relationship
Show Abstract · Added April 8, 2017
The neuropeptide Y receptor (Y R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y R. Despite differences in size and structure, all three antagonists display a similar binding site, including a deep hydrophobic cavity formed by transmembrane helices (TM) 4, 5, and 6, as well as a hydrophobic patch at the top of TM2 and 7. Additionally, we suggest that the antagonists block Q , a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
1 Communities
1 Members
0 Resources
15 MeSH Terms
C-terminal motif of human neuropeptide Y receptor determines internalization and arrestin recruitment.
Wanka L, Babilon S, Burkert K, Mörl K, Gurevich VV, Beck-Sickinger AG
(2017) Cell Signal 29: 233-239
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Amino Acids, Animals, COS Cells, Chlorocebus aethiops, Endocytosis, HEK293 Cells, Humans, Mutant Proteins, Receptors, Neuropeptide Y, Reproducibility of Results, Sequence Alignment, Sequence Deletion, Structure-Activity Relationship, beta-Arrestin 2
Show Abstract · Added March 14, 2018
The human neuropeptide Y receptor is a rhodopsin-like G protein-coupled receptor (GPCR), which contributes to anorexigenic signals. Thus, this receptor is a highly interesting target for metabolic diseases. As GPCR internalization and trafficking affect receptor signaling and vice versa, we aimed to investigate the molecular mechanism of hYR desensitization and endocytosis. The role of distinct segments of the hYR carboxyl terminus was investigated by fluorescence microscopy, binding assays, inositol turnover experiments and bioluminescence resonance energy transfer assays to examine the internalization behavior of hYR and its interaction with arrestin-3. Based on results of C-terminal deletion mutants and substitution of single amino acids, the motif EESEHLPLSTVHTEVSKGS was identified, with glutamate, threonine and serine residues playing key roles, based on site-directed mutagenesis. Thus, we identified the internalization motif for the human neuropeptide Y receptor, which regulates arrestin-3 recruitment and receptor endocytosis.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Discovery of Small-Molecule Modulators of the Human Y4 Receptor.
Sliwoski G, Schubert M, Stichel J, Weaver D, Beck-Sickinger AG, Meiler J
(2016) PLoS One 11: e0157146
MeSH Terms: Allosteric Regulation, Animals, COS Cells, Chlorocebus aethiops, Drug Evaluation, Preclinical, Humans, Ligands, Niclosamide, Receptors, Neuropeptide Y, Small Molecule Libraries, Structure-Activity Relationship
Show Abstract · Added April 8, 2017
The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y₂ Receptor Binding and Activation.
Kaiser A, Müller P, Zellmann T, Scheidt HA, Thomas L, Bosse M, Meier R, Meiler J, Huster D, Beck-Sickinger AG, Schmidt P
(2015) Angew Chem Int Ed Engl 54: 7446-9
MeSH Terms: Amino Acid Sequence, Binding Sites, Humans, Molecular Docking Simulation, Molecular Sequence Data, Neuropeptide Y, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Structure, Secondary, Receptors, Neuropeptide Y
Show Abstract · Added February 5, 2016
Despite recent breakthroughs in the structural characterization of G-protein-coupled receptors (GPCRs), there is only sparse data on how GPCRs recognize larger peptide ligands. NMR spectroscopy, molecular modeling, and double-cycle mutagenesis studies were integrated to obtain a structural model of the peptide hormone neuropeptide Y (NPY) bound to its human G-protein-coupled Y2 receptor (Y2R). Solid-state NMR measurements of specific isotope-labeled NPY in complex with in vitro folded Y2R reconstituted into phospholipid bicelles provided the bioactive structure of the peptide. Guided by solution NMR experiments, it could be shown that the ligand is tethered to the second extracellular loop by hydrophobic contacts. The C-terminal α-helix of NPY, which is formed in a membrane environment in the absence of the receptor, is unwound starting at T(32) to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
1 Communities
2 Members
0 Resources
10 MeSH Terms
Position and length of fatty acids strongly affect receptor selectivity pattern of human pancreatic polypeptide analogues.
Mäde V, Bellmann-Sickert K, Kaiser A, Meiler J, Beck-Sickinger AG
(2014) ChemMedChem 9: 2463-74
MeSH Terms: Amino Acid Sequence, Animals, Anti-Obesity Agents, COS Cells, Chlorocebus aethiops, Fatty Acids, Half-Life, Humans, Kinetics, Ligands, Liver, Molecular Sequence Data, Pancreatic Polypeptide, Receptors, Neuropeptide Y
Show Abstract · Added January 24, 2015
Pancreatic polypeptide (PP) is a satiety-inducing gut hormone targeting predominantly the Y4 receptor within the neuropeptide Y multiligand/multireceptor family. Palmitoylated PP-based ligands have already been reported to exert prolonged satiety-inducing effects in animal models. Here, we suggest that other lipidation sites and different fatty acid chain lengths may affect receptor selectivity and metabolic stability. Activity tests revealed significantly enhanced potency of long fatty acid conjugates on all four Y receptors with a preference of position 22 over 30 at Y1 , Y2 and Y5 receptors. Improved Y receptor selectivity was observed for two short fatty acid analogues. Moreover, [K(30)(E-Prop)]hPP2-36 (15) displayed enhanced stability in blood plasma and liver homogenates. Thus, short chain lipidation of hPP at key residue 30 is a promising approach for anti-obesity therapy because of maintained selectivity and a sixfold increased plasma half-life.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Mutations in arrestin-3 differentially affect binding to neuropeptide Y receptor subtypes.
Gimenez LE, Babilon S, Wanka L, Beck-Sickinger AG, Gurevich VV
(2014) Cell Signal 26: 1523-31
MeSH Terms: Animals, Arrestins, COS Cells, Cell Line, Chlorocebus aethiops, Mutation, Protein Binding, Receptors, Adrenergic, beta, Receptors, Dopamine, Receptors, Muscarinic, Receptors, Neuropeptide Y
Show Abstract · Added February 12, 2015
Based on the identification of residues that determine receptor selectivity in arrestins and the phylogenetic analysis of the arrestin (arr) family, we introduced fifteen mutations of receptor-discriminator residues in arr-3, which were identified previously using mutagenesis, in vitro binding, and BRET-based recruitment assay in intact cells. The effects of these mutations were tested using neuropeptide Y receptors Y1R and Y2R. NPY-elicited arr-3 recruitment to Y1R was not affected by these mutations, or even alanine substitution of all ten residues (arr-3-NCA), which prevented arr-3 binding to other receptors tested so far. However, NCA and two other mutations prevented agonist-independent arr-3 pre-docking to Y1R. In contrast, eight out of 15 mutations significantly reduced agonist-dependent arr-3 recruitment to Y2R. NCA eliminated arr-3 binding to active Y2R, whereas Tyr239Thr reduced it ~7-fold. Thus, manipulation of key residues on the receptor-binding surface generates arr-3 with high preference for Y1R over Y2R. Several mutations differentially affect arr-3 pre-docking and agonist-induced recruitment. Thus, arr-3 recruitment to the receptor involves several mechanistically distinct steps. Targeted mutagenesis can fine-tune arrestins directing them to specific receptors and particular activation states of the same receptor.
Copyright © 2014 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket.
Pedragosa-Badia X, Sliwoski GR, Dong Nguyen E, Lindner D, Stichel J, Kaufmann KW, Meiler J, Beck-Sickinger AG
(2014) J Biol Chem 289: 5846-59
MeSH Terms: Animals, Binding Sites, COS Cells, Chlorocebus aethiops, Crystallography, X-Ray, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Pancreatic Polypeptide, Protein Structure, Quaternary, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Neuropeptide Y
Show Abstract · Added January 24, 2015
Structural characterization of the human Y4 receptor (hY4R) interaction with human pancreatic polypeptide (hPP) is crucial, not only for understanding its biological function but also for testing treatment strategies for obesity that target this interaction. Here, the interaction of receptor mutants with pancreatic polypeptide analogs was studied through double-cycle mutagenesis. To guide mutagenesis and interpret results, a three-dimensional comparative model of the hY4R-hPP complex was constructed based on all available class A G protein-coupled receptor crystal structures and refined using experimental data. Our study reveals that residues of the hPP and the hY4R form a complex network consisting of ionic interactions, hydrophobic interactions, and hydrogen binding. Residues Tyr(2.64), Asp(2.68), Asn(6.55), Asn(7.32), and Phe(7.35) of Y4R are found to be important in receptor activation by hPP. Specifically, Tyr(2.64) interacts with Tyr(27) of hPP through hydrophobic contacts. Asn(7.32) is affected by modifications on position Arg(33) of hPP, suggesting a hydrogen bond between these two residues. Likewise, we find that Phe(7.35) is affected by modifications of hPP at positions 33 and 36, indicating interactions between these three amino acids. Taken together, we demonstrate that the top of transmembrane helix 2 (TM2) and the top of transmembrane helices 6 and 7 (TM6-TM7) form the core of the peptide binding pocket. These findings will contribute to the rational design of ligands that bind the receptor more effectively to produce an enhanced agonistic or antagonistic effect.
1 Communities
1 Members
0 Resources
13 MeSH Terms