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Article10.1096/fasebj.20.5.a1119-b

MT <sub>1</sub> receptor binding pocket insights based on <i>de novo</i> molecular modeling

Martín Indarte,Jeremy Heyman,Jeffry D. Madura,Yi Liu,Wendy Adams,Christopher K. Surratt-2006-03-01-The FASEB Journal
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TL;DRAbstract

Despite the development of therapeutic melatonin analogs, the MT1 melatonin receptor binding pocket is virtually uncharacterized. Here, two de novo modeling approaches were used to detect likely MT1 binding pockets. Surprisingly, the same melatonin binding pocket was identified using the dissimilar docking algorithms of AutoDock and MOE. An asparagine residue in the sixth transmembrane domain (N6.52) has been reported to be important for MT2 ligand binding. De novo modeling suggests that this residue in MT1 would be differentially important for ligand recognition. To test this hypothesis regarding MT1, site-directed mutagenesis replaced N6.52 with an alanine residue in order to disrupt hydrogen-bonding potential while preserving helical structure. Transient expression of N6.52A in COS-7 cells indicated that affinity for [125I]-iodomelatonin was similar to wild type (100 pM). Stable CHO cell lines were created to further characterize this mutant. In initial competition assays, the Ki fo

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Despite the development of therapeutic melatonin analogs, the MT1 melatonin receptor binding pocket is virtually uncharacterized. Here, two de novo modeling approaches were used to detect likely MT1 binding pockets. Surprisingly, the same melatonin binding pocket was identified using the dissimilar docking algorithms of AutoDock and MOE. An asparagine residue in the sixth transmembrane domain (N6.52) has been reported to be important for MT2 ligand binding. De novo modeling suggests that this residue in MT1 would be differentially important for ligand recognition. To test this hypothesis regarding MT1, site-directed mutagenesis replaced N6.52 with an alanine residue in order to disrupt hydrogen-bonding potential while preserving helical structure. Transient expression of N6.52A in COS-7 cells indicated that affinity for [125I]-iodomelatonin was similar to wild type (100 pM). Stable CHO cell lines were created to further characterize this mutant. In initial competition assays, the Ki fo

Keywords

Melatonin receptorMelatoninTransmembrane domainMutantBinding siteAsparagineChemistryDocking (animal)

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