A rhodopsin-based model for melatonin recognition at its G protein-coupled receptor

Navajas, Cecil; Kokkola, Tarja; Poso, Antti; Honka, Nina; Gynther, Jukka; Laitinen, Jarmo T.

doi:10.1016/0014-2999(96)00114-8

Cited by 61 publications

(49 citation statements)

References 32 publications

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“…MT 1 Melatonin Receptor. A rhodopsin-based computer model has been used to propose the molecular structure of the melatonin receptor binding site (Navajas et al, 1996). This particular model has advantages over bacteriorhodopsin-based models for the melatonin receptor binding site Grol and Jansen, 1996), because bacteriorhodopsin is not coupled to G proteins, and its sequence has none of the distinctive features of the GPCR family (Baldwin, 1993).…”

Section: Molecular Structure Of Mt 1 and Mt 2 Melatoninmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

et al. 2010

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Section: Molecular Structure Of Mt 1 and Mt 2 Melatoninmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

et al. 2010

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“…A number of molecular modeling studies of the MLT receptors have been reported [18,[29][30][31][32]. The level of sophistication of these models varies considerably as do the number and diversity of compounds on which they are based and on the building approach.…”

Section: Molecular Modelingmentioning

confidence: 99%

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

1999

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This paper reviews our progress made in characterizing structure-affinity relationships of indole-based melatonin analogs. Evidence is presented suggesting a preferred folded conformation for the amido side chain, almost orthogonal to the plane of indole. A 3D-QSAR comparative molecular field analysis (CoMFA) model, accounting for the observed differences in binding affinity within different classes of melatonergic ligands, and capable of quantitatively predicting the binding affinity of new compounds, is also reported.

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“…Therefore, the binding site of the melatonin receptor appears similar but not identical to those of other rhodopsin-like GPCRs. A recent molecular model proposed for the structure of the melatonin receptor-binding site hypothesized that two TM7 residues, Ser 7.38 and Ala 7.42 , may also be involved in melatonin binding interactions (13); however, site-directed mutagenesis of these residues recently suggested that this was not the case (8). Therefore, apart from His 5.46 , the residues forming the melatonin-binding site remain to be identified.…”

mentioning

confidence: 98%

Chimeric Melatonin mt1 and Melatonin-related Receptors

Conway¹,

Drew²,

Mowat³

et al. 2000

Journal of Biological Chemistry

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Melatonin receptors bind and become activated by melatonin. The melatonin-related receptor, despite sharing considerable amino acid sequence identity with melatonin receptors, does not bind melatonin and is currently an orphan G protein-coupled receptor. To investigate the structure and function of both receptors, we engineered a series of 14 chimeric receptor constructs, allowing us to determine the relative contribution of each transmembrane domain to ligand binding and receptor function. Results identified that when sequences encoding transmembrane domains 1, 2, 3, 5, or 7 of the melatonin mt 1 receptor were replaced by the corresponding domains of the melatonin-related receptor, the resultant chimeric receptors all displayed specific 2-[ 125 I]iodomelatonin binding. Replacement of sequences incorporating transmembrane domains 4 or 6, however, resulted in chimeric receptors that displayed no detectable 2-[ 125 I]iodomelatonin binding. The subsequent testing of a "reverse" chimeric receptor in which sequences encoding transmembrane domains 4 and 6 of the melatonin-related receptor were replaced by the corresponding melatonin mt 1 receptor sequences identified specific 2-[ 125 I]iodomelatonin binding and melatoninmediated modulation of cyclic AMP levels. To further investigate these findings, site-directed mutagenesis was performed on residues within transmembrane domain 6 of the melatonin mt 1 receptor. This identified Gly 258 (Gly 6.55 ) as a critical residue required for high affinity ligand binding and receptor function.Melatonin is the native ligand for high affinity G proteincoupled melatonin receptors (1, 2). There are now almost 20 reported melatonin receptor sequences, which have been classified into three molecular subtypes, mt 1 , MT 2 , and Mel1c (3). Despite classification as molecular subtypes, they all have essentially identical binding affinities for melatonin (K i ϭ ϳ0.5 nM), and each mediates inhibition of stimulated cyclic AMP levels, mainly but not exclusively via the activation of G i proteins (4). During the cloning of the melatonin receptors a homologue, the melatonin-related receptor, was identified, but despite containing 57% amino acid sequence identity with the TM 1 domains of the melatonin mt 1 receptor, it did not bind 2-[ 125 I]iodomelatonin or melatonin (5, 6). The melatonin-related receptor remains an orphan GPCR with no ligand or signal transduction pathway yet identified.The molecular structure and function of the melatonin mt 1 receptor has been investigated by site-directed mutagenesis, identifying the conserved His residue within TM5 as interacting with the 5-methoxy group of melatonin (7,8). Using the nomenclature of Ballesteros and Weinstein (9), this residue is located at position 5.46 (His 5.46 ), which corresponds to a position identified in the binding site of many other rhodopsin-like GPCRs, including Ser 5.46 (amino acid 207) in the hamster ␤ 2 adrenergic receptor (10). Ligand binding to the ␤ 2 adrenergic receptor has also been shown to involve an ionic interaction ...

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A rhodopsin-based model for melatonin recognition at its G protein-coupled receptor

Cited by 61 publications

References 32 publications

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

Chimeric Melatonin mt1 and Melatonin-related Receptors

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