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Adenosine (ADO) is widely distributed in various tissues and organs of the human body, and regulates a variety of important physiological and pathological processes
in the human body by acting on adenosine receptors (ARs).
The ARs family includes four subtypes,A1R, A2A2R, A2BR, andA3R, withA2BR having a weak affinity with adenosine molecules (micromolar level), while the other three receptors have binding capacity at the nanomolar level.
A2BR is expressed in immune cells, fibroblasts, smooth muscle cells and a variety of tumor cells, regulating immunity, cell growth, heart function, etc
.
The adenosine/A2BR signaling pathway has a histoprotective effect in acute disease models, such as myocardial ischemia and acute lung injury
.
The small molecule non-nucleoside ligand BAY 60-6583 is a high-affinity selective agonist ofA2BR with cardioprotective effects
.
in the human body by acting on adenosine receptors (ARs).
The ARs family includes four subtypes,A1R, A2A2R, A2BR, andA3R, withA2BR having a weak affinity with adenosine molecules (micromolar level), while the other three receptors have binding capacity at the nanomolar level.
A2BR is expressed in immune cells, fibroblasts, smooth muscle cells and a variety of tumor cells, regulating immunity, cell growth, heart function, etc
.
The adenosine/A2BR signaling pathway has a histoprotective effect in acute disease models, such as myocardial ischemia and acute lung injury
.
The small molecule non-nucleoside ligand BAY 60-6583 is a high-affinity selective agonist ofA2BR with cardioprotective effects
.
On December 28, 2022, the team of researchers Xu Huaqiang and Xie Xin of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with researcher Yi Jiang of Lingang Laboratory, jointly published the latest research results "Structures of adenosine receptor A2BR bound to endogenous and synthetic agonists" in Cell Discovery
。 The cryo-EM structure of theA2BR receptor family binding endogenous ligand adenosine (ADO) and selective agonist small molecule (BAY 60-6583) and coupling the modified Gs complex was resolved with resolutions of 3.
2 angstroms and 2.
9 angstroms
, respectively.
。 The cryo-EM structure of theA2BR receptor family binding endogenous ligand adenosine (ADO) and selective agonist small molecule (BAY 60-6583) and coupling the modified Gs complex was resolved with resolutions of 3.
2 angstroms and 2.
9 angstroms
, respectively.
This result shows thatA2BR has a highly conserved adenosine ligand-binding pocket
compared to the adenosine receptor family.
Molecular dynamics simulations showed that the binding of ADO to A2B R ligand-recognition pockets had lower stability thanA1Rand A2AR, possibly mediating the relatively low affinity
of ADO forA2R.
Compared to endogenous ADO, BAY 60-6583 has a deeper binding site and forms polar interactions
with amino acids deep in the pocket.
By analyzing the difference between ligand-binding pocket residues in the adenosine family receptor, the researchers found that the 6.
51-position valine (V 6.
51) in theA2BR pocket, while the other members of the adenosine receptor family were all leucine (L6.
51)
at that site.
Leucine has a longer side chain than valine and may cause steric hindrance
on ligand binding.
The researchers reverse-mutated the 6.
51 sites ofA1R/A2A2R, respectively, and found that these mutants all acquired the ability to bind BAY 60-6583 molecules, suggesting that valine at position 6.
51 is a key site forA2BR binding selective
ligands.
The results of this study helped researchers understand the mechanism ofA2BR binding to adenosine and non-nucleoside ligands from the perspective of structure, and laid a structural foundation
for the selective ligand development of adenosine family receptors.
compared to the adenosine receptor family.
Molecular dynamics simulations showed that the binding of ADO to A2B R ligand-recognition pockets had lower stability thanA1Rand A2AR, possibly mediating the relatively low affinity
of ADO forA2R.
Compared to endogenous ADO, BAY 60-6583 has a deeper binding site and forms polar interactions
with amino acids deep in the pocket.
By analyzing the difference between ligand-binding pocket residues in the adenosine family receptor, the researchers found that the 6.
51-position valine (V 6.
51) in theA2BR pocket, while the other members of the adenosine receptor family were all leucine (L6.
51)
at that site.
Leucine has a longer side chain than valine and may cause steric hindrance
on ligand binding.
The researchers reverse-mutated the 6.
51 sites ofA1R/A2A2R, respectively, and found that these mutants all acquired the ability to bind BAY 60-6583 molecules, suggesting that valine at position 6.
51 is a key site forA2BR binding selective
ligands.
The results of this study helped researchers understand the mechanism ofA2BR binding to adenosine and non-nucleoside ligands from the perspective of structure, and laid a structural foundation
for the selective ligand development of adenosine family receptors.
The cryo-EM data in this study were collected
by the Gao Electron Microscopy Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Cai Hongmin, a postdoctoral fellow at Shanghai Institute of Materia Medica, Xu Youwei, an associate researcher, and Guo Shimeng, a postdoctoral fellow, are co-first authors
of the paper.
Researcher Yi Jiang, Xin Xie and Huaqiang Xu are co-corresponding authors, and Shanghai Institute of Materia Medica
.
The work has been funded
by the National Natural Science Foundation of China, the Ministry of Science and Technology, and the Shanghai Municipal Science and Technology Major Project.
by the Gao Electron Microscopy Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Cai Hongmin, a postdoctoral fellow at Shanghai Institute of Materia Medica, Xu Youwei, an associate researcher, and Guo Shimeng, a postdoctoral fellow, are co-first authors
of the paper.
Researcher Yi Jiang, Xin Xie and Huaqiang Xu are co-corresponding authors, and Shanghai Institute of Materia Medica
.
The work has been funded
by the National Natural Science Foundation of China, the Ministry of Science and Technology, and the Shanghai Municipal Science and Technology Major Project.
Full text link:
Figure 1: A-B, ADO and BAY 60-6583 COMPLEX STRUCTURES WITHA2BRand Gsproteins; e, dynamics simulation of adenosine receptor binding to adenosine pockets; f, adenosine receptor family orthoptic pocket amino acids; g, potential steric hindrance
between BAY 60-6583 and L6.
51.
Effects of leucine/valine at position 6.
51 of wild-type and mutant ARs on BAY 60-6583
.
between BAY 60-6583 and L6.
51.
Effects of leucine/valine at position 6.
51 of wild-type and mutant ARs on BAY 60-6583
.
(Contributing department: Xu Huaqiang research group)
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