Dataset Information

Identification of natural products as novel ligands for the human 5-HT2C receptor.

ABSTRACT: G protein-coupled receptors (GPCRs) constitute the largest human protein family with over 800 members, which are implicated in many important medical conditions. Serotonin receptors belong to the aminergic GPCR subfamily and play important roles in physiological and psychological activities. Structural biology studies have revealed the structures of many GPCRs in atomic details and provide the basis for the identification and investigation of the potential ligands, which interact with and modulate the receptors. Here, an integrative approach combining a focused target-specific natural compound library, a thermal-shift-based screening method, affinity mass spectrometry, molecular docking, and in vitro as well as in vivo functional assay, was applied to identify (-)-crebanine and several other aporphine alkaloids as initial hits for a human serotonin receptor subtype, the 5-HT2C receptor. Further studies illuminated key features of their binding affinity, downstream signaling and tissue reaction, providing a molecular explanation for the interaction between (-)-crebanine and human 5-HT2C receptor.

SUBMITTER: Peng Y

PROVIDER: S-EPMC5860131 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Identification of natural products as novel ligands for the human 5-HT<sub>2C</sub> receptor.

Peng Yao Y Zhao Simeng S Wu Yiran Y Cao Haijie H Xu Yueming Y Liu Xiaoyan X Shui Wenqing W Cheng Jianjun J Zhao Suwen S Shen Ling L Ma Jun J Quinn Ronald J RJ Stevens Raymond C RC Zhong Guisheng G Liu Zhi-Jie ZJ

Biophysics reports 20180309 1

G protein-coupled receptors (GPCRs) constitute the largest human protein family with over 800 members, which are implicated in many important medical conditions. Serotonin receptors belong to the aminergic GPCR subfamily and play important roles in physiological and psychological activities. Structural biology studies have revealed the structures of many GPCRs in atomic details and provide the basis for the identification and investigation of the potential ligands, which interact with and modula ...[more]

PMID: 29577069

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Project description:Many bioactive natural products are glycosylated compounds in which the sugar components usually participate in interaction and molecular recognition of the cellular target. Therefore, the presence of sugar moieties is important, in some cases essential, for bioactivity. Searching for novel glycosylated bioactive compounds is an important aim in the field of the research for natural products from actinomycetes. A great majority of these sugar moieties belong to the 6-deoxyhexoses and share two common biosynthetic steps catalyzed by a NDP-D-glucose synthase (GS) and a NDP-D-glucose 4,6-dehydratase (DH). Based on this fact, seventy one Streptomyces strains isolated from the integument of ants of the Tribe Attini were screened for the presence of biosynthetic gene clusters (BGCs) for glycosylated compounds. Total DNAs were analyzed by PCR amplification using oligo primers for GSs and DHs and also for a NDP-D-glucose-2,3-dehydratases. Amplicons were used in gene disruption experiments to generate non-producing mutants in the corresponding clusters. Eleven mutants were obtained and comparative dereplication analyses between the wild type strains and the corresponding mutants allowed in some cases the identification of the compound coded by the corresponding cluster (lobophorins, vicenistatin, chromomycins and benzanthrins) and that of two novel macrolactams (sipanmycin A and B). Several strains did not show UPLC differential peaks between the wild type strain and mutant profiles. However, after genome sequencing of these strains, the activation of the expression of two clusters was achieved by using nutritional and genetic approaches leading to the identification of compounds of the cervimycins family and two novel members of the warkmycins family. Our work defines a useful strategy for the identification new glycosylated compounds by a combination of genome mining, gene inactivation experiments and the activation of silent biosynthetic clusters in Streptomyces strains.

Dataset Information

Identification of natural products as novel ligands for the human 5-HT2C receptor.

Publications

Identification of natural products as novel ligands for the human 5-HT<sub>2C</sub> receptor.

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