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Metabolic diseases such as diabetes, fatty liver and obesity have become a major "killer" affecting human health, and studies have shown that some orphan receptors may be important targets for the treatment of these disease.
GPR119, also known as Glucose-dependent insulinotropic receptor, is an orphan receptor in the G protein-coupled receptor (GPCR) superfamil.
Due to its role in the regulation of glucose metabolism, GPR119 is considered as a potential drug target for the treatment of metabolic diseases such as diabetes, fatty liver and obesit.
GPR119 is mainly distributed in islet beta cells and gastrointestinal L cells, and regulates glucose-dependent insulinotropic secretio.
Activation of GPR119 can stimulate the secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP), two hormones that are important in regulating the balance of glucose metabolism in the bod.
GPR119, also known as Glucose-dependent insulinotropic receptor, is an orphan receptor in the G protein-coupled receptor (GPCR) superfamil.
Due to its role in the regulation of glucose metabolism, GPR119 is considered as a potential drug target for the treatment of metabolic diseases such as diabetes, fatty liver and obesit.
GPR119 is mainly distributed in islet beta cells and gastrointestinal L cells, and regulates glucose-dependent insulinotropic secretio.
Activation of GPR119 can stimulate the secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP), two hormones that are important in regulating the balance of glucose metabolism in the bod.
In recent years, more and more small-molecule agonists of GPR119 have been developed as clinical drugs for the development of oral treatment of diabete.
However, the lack of understanding of GPR119 function and activation mechanism has limited the development of small molecule drugs targeting GPR119. Therefore, more in-depth molecular level research on this target has become an important research hotspot in this field, and revealing the interaction mechanism of GPR119 with endogenous ligands and drug molecules has also become an important scientific issu.
In addition, GPR119 has always been considered to have a high "self-activation" activity, but the reason and structural basis of this "self-activation" are still unclea.
However, the lack of understanding of GPR119 function and activation mechanism has limited the development of small molecule drugs targeting GPR119. Therefore, more in-depth molecular level research on this target has become an important research hotspot in this field, and revealing the interaction mechanism of GPR119 with endogenous ligands and drug molecules has also become an important scientific issu.
In addition, GPR119 has always been considered to have a high "self-activation" activity, but the reason and structural basis of this "self-activation" are still unclea.
On August 15, 2022, researcher Xu Huaqiang and Xie Xin of Shanghai Institute of Materia Medica , Chinese Academy of Sciences, together with Jiang Yi , researcher of Lingang Laboratory , published the latest research result "Structural identification of lysophosphatidylcholines as activating ligands for activating ligands for" in Nature Structural & Molecular Biology.
orphan receptor GPR119”.
The study found that GPR119 can bind to and be activated by lysophosphatidylcholines (LPC) in the cell membrane without adding any exogenous ligands, which perfectly explains the so-called "self-activation" phenomenon of some receptors It is actually caused by an unknown endogenous ligand.
The study also analyzed the cryo-EM structure of the complex between GPR119 and the clinical stage small molecule drug candidate APD668, and clarified the molecular mechanism of receptor coupling to downstream Gs signaling proteins.
orphan receptor GPR119”.
The study found that GPR119 can bind to and be activated by lysophosphatidylcholines (LPC) in the cell membrane without adding any exogenous ligands, which perfectly explains the so-called "self-activation" phenomenon of some receptors It is actually caused by an unknown endogenous ligand.
The study also analyzed the cryo-EM structure of the complex between GPR119 and the clinical stage small molecule drug candidate APD668, and clarified the molecular mechanism of receptor coupling to downstream Gs signaling proteins.
To study the structure of GPR119, the researchers expressed and purified a complex sample of the human GPR119 receptor and Gs protein trimer from insect cells, and resolved the complexation of GPR119 and Gs protein without adding small molecule ligand.
structure with a resolution of 1 angstrom.
Through structural observation, the researchers unexpectedly found that there is a narrow and long density of small molecule ligands in the ligand-binding pocket of the recepto.
To identify the species of this small molecule, the researchers subjected a sample of the complex to mass spectrometry, which showed that the small molecule density belongs to lysophosphatidylcholine (LPC) with a single-chain hydrophobic tai.
The researchers further verified the activation of GPR119 by different types of lysophospholipids at the cellular level, and the results showed that different types of lysophospholipids had different degrees of activation of GPR119.
structure with a resolution of 1 angstrom.
Through structural observation, the researchers unexpectedly found that there is a narrow and long density of small molecule ligands in the ligand-binding pocket of the recepto.
To identify the species of this small molecule, the researchers subjected a sample of the complex to mass spectrometry, which showed that the small molecule density belongs to lysophosphatidylcholine (LPC) with a single-chain hydrophobic tai.
The researchers further verified the activation of GPR119 by different types of lysophospholipids at the cellular level, and the results showed that different types of lysophospholipids had different degrees of activation of GPR119.
FigureCryo-EM structures of GPR119/Gs in complex with lysophosphatidylcholine (LPC) (a) or clinical small molecule drug candidate APD668 (b.
The ligand-binding pocket of GPR119 can be divided into two parts: hydrophobic and hydrophili.
The hydrophobic pocket runs through the extracellular region and the central position of the receptor, and mainly binds to the hydrophobic tail of LPC; while the hydrophilic pocket extends to the extracellular region and mainly binds to the hydrophilic head of LP.
Notably, the pocket of GPR119 is elongated, forming an opening in the central part of the receptor, allowing the ligand-binding pocket to communicate with the cell membran.
The formation of this opening is related to the unique structure of transmembrane helix 5 (TM5) of GPR119. Near the middle position (5x50) of TM5 of GPR119, the amino acid sequence of GPR119 exhibits a staggered one position compared with other Class A GPCRs in structure, thus forming a unique opening structur.
This open structure not only provides binding space for longer single-chain phospholipids, but also provides another potential ligand entranc.
By means of molecular docking, the researchers proposed a binding site near the opening that may constitute an allosteric regulator, and explored the potential binding mode of Gordonoside F, a polysaccharide natural product with an appetite-controlling effect, to this allosteric sit.
The hydrophobic pocket runs through the extracellular region and the central position of the receptor, and mainly binds to the hydrophobic tail of LPC; while the hydrophilic pocket extends to the extracellular region and mainly binds to the hydrophilic head of LP.
Notably, the pocket of GPR119 is elongated, forming an opening in the central part of the receptor, allowing the ligand-binding pocket to communicate with the cell membran.
The formation of this opening is related to the unique structure of transmembrane helix 5 (TM5) of GPR119. Near the middle position (5x50) of TM5 of GPR119, the amino acid sequence of GPR119 exhibits a staggered one position compared with other Class A GPCRs in structure, thus forming a unique opening structur.
This open structure not only provides binding space for longer single-chain phospholipids, but also provides another potential ligand entranc.
By means of molecular docking, the researchers proposed a binding site near the opening that may constitute an allosteric regulator, and explored the potential binding mode of Gordonoside F, a polysaccharide natural product with an appetite-controlling effect, to this allosteric sit.
FigureThe binding pocket of LPC in GPR119 and the effect of key amino acid mutations on receptor activit.
In order to study the binding mechanism of high-affinity ligands and clinical candidate small molecule drugs to GPR119, the researchers solved the structure of the representative agonist APD668 in complex with GPR119 with a resolution of 8 angstrom.
The researchers found that the more rigid structural backbone of APD668 mainly occupies the hydrophobic pocket of GPR119 and forms stronger interactions with amino acids in this pocket, providing higher affinity for the ligan.
In addition, the researchers found that the activation switch (Toggle Switch) residue W238 48 of GPR119 exhibited a different deflection mode from other receptors, and found a water molecule near this residue to form hydrogen bonds with surrounding residues, stabilizing the receptor's activation conformatio.
The researchers found that the more rigid structural backbone of APD668 mainly occupies the hydrophobic pocket of GPR119 and forms stronger interactions with amino acids in this pocket, providing higher affinity for the ligan.
In addition, the researchers found that the activation switch (Toggle Switch) residue W238 48 of GPR119 exhibited a different deflection mode from other receptors, and found a water molecule near this residue to form hydrogen bonds with surrounding residues, stabilizing the receptor's activation conformatio.
In conclusion, this study is the first to report the molecular mechanism of the orphan receptor GPR119 preferentially binding to LPC, and propose that some of the so-called "self-activating" receptors may be caused by binding to unknown ligand.
The structure of the source ligand LPC and the clinical candidate small molecule drug APD668 revealed the structural basis of GPR119 activation by small molecules; at the same time, the unique structural features of GPR119 and the binding site of potential allosteric regulators were discovered, which is the basis for targeting GPR119 Metabolic disease drug development provides an important structural basi.
The structure of the source ligand LPC and the clinical candidate small molecule drug APD668 revealed the structural basis of GPR119 activation by small molecules; at the same time, the unique structural features of GPR119 and the binding site of potential allosteric regulators were discovered, which is the basis for targeting GPR119 Metabolic disease drug development provides an important structural basi.
The research team of researchers Xu Huaqiang and Xie Xinof Shanghai Institute of Materia Medica and researcher Jiang Yi of Lingang Laboratory cooperated and worked together to solve this problem, and completed with the assistance of academician Jiang Hualiang and researcher Zhou Hu of Shanghai Institute of Materia Medica.
D.
Xu Peiyu (now a postdoctoral fellow at MIT), D.
Huang Sijie (now a postdoctoral fellow at UCSF), Shanghai Institute of Materia Medica, D.
Shimeng Guo , and postdoctoral fellow at the Hangzhou Institute for Advanced Study of UCAS are the co-first authors of this article.
This work was funded by the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Major Project, and the Chinese Academy of Sciences' Strategic Pilot Science and Technology Project.
D.
Xu Peiyu (now a postdoctoral fellow at MIT), D.
Huang Sijie (now a postdoctoral fellow at UCSF), Shanghai Institute of Materia Medica, D.
Shimeng Guo , and postdoctoral fellow at the Hangzhou Institute for Advanced Study of UCAS are the co-first authors of this article.
This work was funded by the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Major Project, and the Chinese Academy of Sciences' Strategic Pilot Science and Technology Project.
URL:DOI: 11038/s41594-022-00816-5
(Contributed by: Xu Huaqiang's research group)
