EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders.
ジャーナル・号・ページ	Proc Natl Acad Sci U S A, Vol. 122, Issue 24, Page e2422082122, Year 2025
掲載日	2025年6月17日
著者	Marco C Miotto / Estefania Luna-Figueroa / Carl Tchagou / Laith Bahlouli / Steven Reiken / Haikel Dridi / Yang Liu / Gunnar Weninger / Andrew R Marks /
PubMed 要旨	Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance ...Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.
リンク	Proc Natl Acad Sci U S A / PubMed:40512792 / PubMed Central
手法	EM (単粒子)
解像度	2.12 - 4.49 Å
構造データ	EMDB-47336: Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin - focused map on xanthine 手法: EM (単粒子) / 解像度: 2.38 Å EMDB-47357: Structure of RyR1 in the primed state in the presence of caffeine - focused map (reprocessed from EMPIAR-10997) 手法: EM (単粒子) / 解像度: 2.12 Å 47385 9e18 EMDB-47385, PDB-9e18: Structure of RyR1 in the primed state in the presence of pentoxifylline 手法: EM (単粒子) / 解像度: 2.68 Å 47386 9e19 EMDB-47386, PDB-9e19: Structure of RyR1 in the open state in the presence of pentoxifylline 手法: EM (単粒子) / 解像度: 4.04 Å 47387 9e1a EMDB-47387, PDB-9e1a: Structure of RyR1 in the primed state in the presence of dyphylline 手法: EM (単粒子) / 解像度: 3.35 Å 47388 9e1b EMDB-47388, PDB-9e1b: Structure of RyR1 in the open state in the presence of dyphylline 手法: EM (単粒子) / 解像度: 4.49 Å 47389 9e1c EMDB-47389, PDB-9e1c: Structure of RyR1 in the primed state in the presence of IBMX 手法: EM (単粒子) / 解像度: 2.63 Å 47390 9e1d EMDB-47390, PDB-9e1d: Structure of RyR1 in the primed state in the presence of enprofylline 手法: EM (単粒子) / 解像度: 2.76 Å 47391 9e1e EMDB-47391, PDB-9e1e: Structure of RyR1 in the primed state in the presence of uracil 手法: EM (単粒子) / 解像度: 2.92 Å 47392 9e1f EMDB-47392, PDB-9e1f: Structure of RyR1 in the primed state in the presence of allopurinol 手法: EM (単粒子) / 解像度: 3.03 Å 47393 9e1g EMDB-47393, PDB-9e1g: Structure of RyR1 in the primed state in the presence of oxypurinol 手法: EM (単粒子) / 解像度: 3.17 Å 47394 9e1h EMDB-47394, PDB-9e1h: Structure of RyR1 in the primed state in the presence of oxopyricid 手法: EM (単粒子) / 解像度: 3.26 Å 47395 9e1i EMDB-47395, PDB-9e1i: Structure of RyR1 in the open state in the presence of oxopyricid 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-47396: Structure of RyR1 in the primed state in the presence of pentoxifylline, focused refinement 手法: EM (単粒子) / 解像度: 2.35 Å EMDB-47397: Structure of RyR1 in the open state in the presence of pentoxifylline, focused refinement 手法: EM (単粒子) / 解像度: 3.49 Å EMDB-47398: Structure of RyR1 in the primed state in the presence of dyphylline, focused refinement 手法: EM (単粒子) / 解像度: 3.14 Å EMDB-47399: Structure of RyR1 in the open state in the presence of dyphylline, focused refinement 手法: EM (単粒子) / 解像度: 4.16 Å EMDB-47400: Structure of RyR1 in the primed state in the presence of IBMX, focused refinement 手法: EM (単粒子) / 解像度: 2.34 Å EMDB-47401: Structure of RyR1 in the primed state in the presence of enprofylline, focused refinement 手法: EM (単粒子) / 解像度: 2.42 Å EMDB-47402: Structure of RyR1 in the primed state in the presence of uracil, focused refinement 手法: EM (単粒子) / 解像度: 2.47 Å EMDB-47403: Structure of RyR1 in the primed state in the presence of allopurinol, focused refinement 手法: EM (単粒子) / 解像度: 2.56 Å EMDB-47404: Structure of RyR1 in the primed state in the presence of oxypurinol, focused refinement 手法: EM (単粒子) / 解像度: 2.69 Å EMDB-47405: Structure of RyR1 in the primed state in the presence of oxopyricid, focused refinement 手法: EM (単粒子) / 解像度: 2.64 Å EMDB-47406: Structure of RyR1 in the open state in the presence of oxopyricid, focused refinement 手法: EM (単粒子) / 解像度: 2.65 Å PDB-9e17: Structure of RyR1 in the primed state in the presence of caffeine (reprocessed/reanalyzed from EMPIAR-10997, 7TZC, EMD-26205) 手法: ELECTRON MICROSCOPY / 解像度: 2.45 Å
化合物	ChemComp-CA: Unknown entry ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, エネルギー貯蔵分子YM ChemComp-ZN: Unknown entry ChemComp-CFF: CAFFEINE / 薬剤YM ChemComp-KVR: 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid ChemComp-L9R: (2S)-3-(octadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / SOPC, リン脂質YM ChemComp-HOH: WATER ChemComp-PNX: 3,7-DIMETHYL-1-(5-OXOHEXYL)-3,7-DIHYDRO-1H-PURINE-2,6-DIONE PDB-1bd2: COMPLEX BETWEEN HUMAN T-CELL RECEPTOR B7, VIRAL PEPTIDE (TAX) AND MHC CLASS I MOLECULE HLA-A 0201 ChemComp-IBM: 3-ISOBUTYL-1-METHYLXANTHINE PDB-1bd3: STRUCTURE OF THE APO URACIL PHOSPHORIBOSYLTRANSFERASE, 2 MUTANT C128V ChemComp-URA: URACIL PDB-1bd4: UPRT-URACIL COMPLEX ChemComp-141: Oxypurinol PDB-1bd5*: Unknown entry
由来	homo sapiens (ヒト) oryctolagus cuniculus (ウサギ)
キーワード	TRANSPORT PROTEIN / calcium channel / sarcoplasmic reticulum