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-Structure paper
| タイトル | Structural insights into the agonist selectivity of the adenosine A receptor. |
|---|---|
| ジャーナル・号・ページ | Nat Commun, Vol. 15, Issue 1, Page 9294, Year 2024 |
| 掲載日 | 2024年11月7日 |
著者 | Hidetaka S Oshima / Akiko Ogawa / Fumiya K Sano / Hiroaki Akasaka / Tomoyoshi Kawakami / Aika Iwama / Hiroyuki H Okamoto / Chisae Nagiri / Fan-Yan Wei / Wataru Shihoya / Osamu Nureki / ![]() |
| PubMed 要旨 | Adenosine receptors play pivotal roles in physiological processes. Adenosine A receptor (AR), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important ...Adenosine receptors play pivotal roles in physiological processes. Adenosine A receptor (AR), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of AR-selective agents. Recently, we identified RNA-derived N-methyladenosine (mA) as an endogenous agonist for AR, suggesting the relationship between RNA-derived modified adenosine and AR. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of AR, especially for AR-selective agonists such as mA and namodenoson, remained elusive. Here, we identify tRNA-derived N-isopentenyl adenosine (iA) as an AR-selective ligand via screening of modified nucleosides against the adenosine receptors. Like mA, iA is found in the human body and may be an endogenous AR ligand. Our cryo-EM analyses elucidate the AR-G complexes bound to adenosine, 5'-N-ethylcarboxamidoadenosine (NECA), mA, iA, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (mA), 3.28 Å (iA), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of AR. We further conduct structure-guided engineering of mA-insensitive AR, which may aid future research targeting mA and AR, providing a molecular basis for future drug discovery. |
リンク | Nat Commun / PubMed:39511145 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 2.75 - 3.66 Å |
| 構造データ | EMDB-39278, PDB-8yh0: EMDB-39279, PDB-8yh2: EMDB-39280, PDB-8yh3: EMDB-39281, PDB-8yh5: EMDB-39282, PDB-8yh6: ![]() EMDB-61664: A3R-Gi complex bound to NECA (G protein focused) ![]() EMDB-61666: A3R-Gi complex bound to NECA (receptor focused) ![]() EMDB-61668: A3R-Gi complex bound to adenosine (receptor focused) ![]() EMDB-61670: A3R-Gi complex bound to adenosine (G protein focused) ![]() EMDB-61673: A3R-Gi complex bound to m6a (receptor focused) ![]() EMDB-61674: A3R-Gi complex bound to NECA (G protein focused) ![]() EMDB-61675: A3R-Gi complex bound to i6a (receptor focused) ![]() EMDB-61676: A3R-Gi complex bound to i6a (G protein focused) ![]() EMDB-61677: A3R-Gi complex bound to namodenoson (receptor focused) ![]() EMDB-61678: A3R-Gi complex bound to namodenoson (G protein focused) |
| 化合物 | ![]() ChemComp-NEC: ![]() ChemComp-ADN: ![]() ChemComp-6MD: ![]() ChemComp-ZIR: ![]()
ChemComp-XS0: |
| 由来 |
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キーワード | SIGNALING PROTEIN / GPCR / complex / adenosine receptor / adenosine / g protein |
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homo sapiens (ヒト)
human orthopneumovirus (ウイルス)
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