Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites

Du, Ping; Salon, John; Tamm, Joseph A.; Hou, Cuifen; Cui, Weili; Walker, Mary W.; Adham, Nika; Dhanoa, Dale; Islam, Imadul; Vaysse, Pierre J.‐J.; Dowling, B.; Shifman, Yelena; Boyle, N.; Rueger, H.; Schmidlin, Tibur; Yamaguchi, Yuki; Branchek, Theresa A.; Weinshank, R. L.; Gluchowski, Charles

doi:10.1093/protein/10.2.109

Cited by 53 publications

(55 citation statements)

References 19 publications

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“…In contrast, a few other investigators have found that peptide agonists and peptide or nonpeptidic antagonists have overlapping binding sites on their receptors, including the B 2 bradykinin (43), the ␤-adrenergic (44), the cholecystokinin (45), and the neuropeptide Y Y1 receptors (46). These differences may be attributed to elucidation of only a subset out of multiple interaction sites between ligand and receptor, especially in the case of intermediate-size peptide ligands.…”

Section: Contact Sites Of a Pthrp Agonist And An Antagonistmentioning

confidence: 98%

Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor

Behar¹,

Bisello

Bitan

et al. 2000

Journal of Biological Chemistry

106

140

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Analogs of parathyroid hormone (PTH)- The parathyroid hormone (PTH)1 /PTH-related protein (PTHrP) receptor (PTH1R) is a G protein-coupled, seven-transmembrane domain-containing receptor (GPCR) activated equipotently by two distinct hormones, PTH and PTHrP (1, 2). Although acting through the same receptor, these hormones have different physiological functions: PTH is a regulator of blood calcium levels (3), whereas PTHrP is an autocrine/paracrine factor involved in skeletal and cartilage development (4, 5). The PTH1R is a member of the glucagon/secretin/calcitonin subfamily of GPCRs (2). It is coupled to both adenylyl cyclase (AC)/cyclic AMP and phospholipase C/inositol 1,4,5-trisphosphate/cytosolic calcium intracellular signaling pathways (6 -8).Extensive efforts have been focused on investigating the structural basis for hormone recognition by PTH1R. These lines of research have identified regions in both the ligands and the receptor required for binding and signaling. On one hand, the mutagenesis approach, generating chimeric, mutated, or truncated receptors, has established that multiple receptor domains are involved in the complex interaction with the ligands, including the N-terminal extracellular tail, extracellular loops, and transmembrane domains (TMDs) (9 -11). On the other hand, structure-function studies of the hormones and their analogs have revealed structural determinants required for interaction with the receptor. These studies have identified the C-terminal region of PTH-(1-34) and PTHrP-(1-34) as the principal binding domain (12-14), which is also required for activation of protein kinase C (15, 16). The N-terminal 1-6 sequence of either ligand was found to function as the principal activation domain (Ref. 17 and references therein).The complementary biochemical approach of photoaffinity cross-linking has been utilized to examine directly ligand-receptor bimolecular interactions through the generation of covalently linked radiolabeled ligand-receptor photoconjugates. Here, we report the evaluation of a series of photoreactive analogs of PTHrP in order to probe the nature of receptor interaction with the principal activation domain of the hormone (residues 1-6).

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Section: Contact Sites Of a Pthrp Agonist And An Antagonistmentioning

confidence: 98%

Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor

Behar¹,

Bisello

Bitan

et al. 2000

Journal of Biological Chemistry

106

140

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“…The antagonist binding site at the Y 1 -receptor has been investigated by the combination of sitedirected mutagenesis and molecular modeling studies (Plate 1) [57,73]. The finding that a large number of mutants maintained affinity for both NPY and BIBP3226, or lost it for both of them, suggests the presence of an overlapping binding site of the agonist and the antagonist.…”

Section: Antagonistsmentioning

confidence: 99%

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

2000

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Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to the NPY hormone family and activate a class of receptors called the Y-receptors, and also belong to the large superfamily of the G-protein coupled receptors. Structure-affinity and structure-activity relationship studies of peptide analogs, combined with studies based on site-directed mutagenesis and anti-receptor antibodies, have given insight into the individual characterization of each receptor subtype relative to its interaction with the ligand, as well as to its biological function. A number of selective antagonists at the Y1-receptor are available whose structures resemble that of the C-terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in vivo investigations of the NPY-induced increase in food intake. Y2-receptor selective agonists are the analog cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY and the TASP molecule containing two units of the NPY segment 21-36. Now the first antagonist with nanomolar affinity for the Y2-receptor is also known, BIIE0246. So far, the native peptide PP has been shown to be the most potent ligand at the Y4-receptor. However, by the design of PP/NPY chimera, some analogs have been found that bind not only to the Y4-, but also to the Y5-receptor with subnanomolar affinities, and are as potent as NPY at the Y1-receptor. For the characterization of the Y5-receptor in vitro and in vivo, a new class of highly selective agonists is now available. This consists of analogs of NPY and of PP/NPY chimera which all contain the motif Ala31-Aib32. This motif has been shown to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be the key motif for high Y5-receptor selectivity. The results of feeding experiments in rats treated with the first highly specific Y5-receptor agonists support the hypothesis that this receptor plays a role in the NPY-induced stimulation of food intake. In conclusion, the selective compounds for the different Y receptor subtypes known so far are promising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors.

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“…The NMS and Ach binding sites overlap in that the cationic headgroups of NMS and Ach bind within the same charge-stabilized aromatic cage of the receptor, but Ach has a compact acetoxy side chain and cannot replicate the stabilizing interhelical interactions provided by the bulky side-chains of NMS (for review, see Lu et al, 2002). In the neuropeptide Y (NPY) receptor, the 36-amino acid C-terminal amidated neuropeptide NPY and a small nonpeptide NPY1 antagonist, BIBP3226, seem to share residues for interactions within the transmembrane regions of the receptor, including Gln-120 (3.32), Asn-283 (6.55), and His-306 (7.39), which are in the same position of key residues for ligand binding of other peptide and biogenic amine receptors (Du et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

A Model of Inverse Agonist Action at Thyrotropin-Releasing Hormone Receptor Type 1: Role of a Conserved Tryptophan in Helix 6

Lu¹,

Huang²,

Worthington³

et al. 2004

Mol Pharmacol

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A binding pocket for thyrotropin-releasing hormone (TRH) within the transmembrane helices of the TRH receptor type 1 (TRH-R1) has been identified based on experimental evidence and computer simulations. To determine the binding site for a competitive inverse agonist, midazolam, three of the four residues that directly contact TRH and other residues that restrain TRH-R1 in an inactive conformation were screened by mutagenesis and binding assays. We found that two residues that directly contact TRH, Asn-110 in transmembrane helix 3 (3.37) and Arg-306 in transmembrane helix 7 (7.39), were important for midazolam binding but another, Tyr-282 in transmembrane helix 6 (6.51), was not. A highly conserved residue, Trp-279 in transmembrane helix 6 (6.48), which was reported to be critical in stabilizing TRH-R1 in an inactive state but not for TRH binding, was critical for midazolam binding. We used our previous model of the unoccupied TRH-R1 to generate a model of the TRH-R1/midazolam complex. The experimental results and the molecular model of the complex suggest that midazolam binds to TRH-R1 within a transmembrane helical pocket that partially overlaps the TRH binding pocket. This result is consistent with the competitive antagonism of midazolam binding. We suggest that the mechanism of inverse agonism effected by midazolam involves its direct interaction with Trp-279, which contributes to the stabilization of the inactive conformation of TRH-R1.Seven transmembrane-spanning receptors (7TMRs) comprise one of the largest protein families in mammalian genomes that transduce a variety of signals across cell-surface membranes to activate numerous cellular responses. Because of the involvement of the 7TMRs in many physiological processes, they have been selected as targets for many therapeutic drugs. All 7TMRs share a putative topological structure, but the molecular details of receptor conformational change upon agonist and inverse agonist binding that lead to activation and inactivation, respectively, have not yet been fully understood. For the last decade, intensive research has been focused on identifying receptor agonist binding sites and the dynamic conformational changes induced upon agonist binding (Osman et al., 1999). However, data about the binding of inverse agonists and the inactivation mechanism of 7TMRs are more limited. Interpretations of the results of these studies have been made more complex because the three-dimensional structure of only a single 7TMR, bovine rhodopsin, has been solved by X-ray crystallography (Palczewski et al., 2000).Thyrotropin-releasing hormone (TRH) is a tripeptide pyroGlu-His-Pro-amide that is synthesized and released from the hypothalamus to regulate pituitary hormone levels. TRH functions as a neurotransmitter/neuromodulator in the central and peripheral nervous systems also. TRH binds to specific 7TMRs, TRH receptors (TRH-Rs), and induces a cellular response through G-protein-related signaling pathways. The three-dimensional structure of TRH receptor subtype-1 (TRH-R1) a...

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Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites

Cited by 53 publications

References 19 publications

Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor

Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

A Model of Inverse Agonist Action at Thyrotropin-Releasing Hormone Receptor Type 1: Role of a Conserved Tryptophan in Helix 6

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