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	High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.
ジャーナル・号・ページ	Nat Commun, Vol. 15, Issue 1, Page 2265, Year 2024
掲載日	2024年3月13日
著者	Victoria I Cushing / Adrian F Koh / Junjie Feng / Kaste Jurgaityte / Alexander Bondke / Sebastian H B Kroll / Marion Barbazanges / Bodo Scheiper / Ash K Bahl / Anthony G M Barrett / Simak Ali / Abhay Kotecha / Basil J Greber /
PubMed 要旨	Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to ...Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.
リンク	Nat Commun / PubMed:38480681 / PubMed Central
手法	EM (単粒子)
解像度	1.7 - 4.9 Å
構造データ	17129 8orm EMDB-17129, PDB-8orm: Cryo-EM structure of CAK-THZ1 手法: EM (単粒子) / 解像度: 1.9 Å EMDB-17470: Rapid screening cryo-EM map of CAK bound to ICEC0943 (grid VC1-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-17471: Rapid screening cryo-EM map of CAK bound to ICEC0943 (grid VC1-2, 1hr collection) 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-17472: Rapid screening cryo-EM map of CAK bound to ICEC0768 (grid VC2-1, 1hr collection) 手法: EM (単粒子) / 解像度: 4.3 Å EMDB-17473: Rapid screening cryo-EM map of CAK bound to ICEC0768 (grid VC2-2, 1hr collection) 手法: EM (単粒子) / 解像度: 4.9 Å EMDB-17474: Rapid screening cryo-EM map of CAK bound to ICEC0914 (grid VC3-1, 1hr collection) 手法: EM (単粒子) / 解像度: 4.5 Å EMDB-17475: Rapid screening cryo-EM map of CAK bound to ICEC0914 (grid VC3-2, 1hr collection) 手法: EM (単粒子) / 解像度: 4.1 Å EMDB-17476: Rapid screening cryo-EM map of CAK bound to dinaciclib (grid VC4-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-17477: Rapid screening cryo-EM map of CAK bound to dinaciclib (grid VC4-2, 1hr collection) 手法: EM (単粒子) / 解像度: 4.0 Å EMDB-17478: Rapid screening cryo-EM map of CAK bound to ICEC0510-R (grid VC6-3, 1hr collection) 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-17479: Rapid screening cryo-EM map of CAK bound to ICEC0510-R (grid VC6-4, 1hr collection) 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-17480: Rapid screening cryo-EM map of CAK bound to ICEC0510-S (grid VC7-3, 1hr collection) 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-17481: Rapid screening cryo-EM map of CAK bound to ICEC0510-S (grid VC7-4, 1hr collection) 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-17482: Rapid screening cryo-EM map of CAK bound to BS-181 (grid VC8-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.7 Å EMDB-17483: Rapid screening cryo-EM map of CAK bound to BS-181 (grid VC8-2, 1hr collection) 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-17484: Rapid screening cryo-EM map of CAK bound to BS-194 (grid VC9-3, 1hr collection) 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-17485: Rapid screening cryo-EM map of CAK bound to BS-194 (grid VC9-4, 1hr collection) 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-17486: Rapid screening cryo-EM map of CAK bound to ICEC0574 (grid VC11-3, 1hr collection) 手法: EM (単粒子) / 解像度: 4.1 Å EMDB-17487: Rapid screening cryo-EM map of CAK bound to ICEC0574 (grid VC11-4, 1hr collection) 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-17488: Rapid screening cryo-EM map of CAK bound to ICEC0829 (grid VC12-3, 1hr collection) 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-17489: Rapid screening cryo-EM map of CAK bound to ICEC0829 (grid VC12-4, 1hr collection) 手法: EM (単粒子) / 解像度: 3.7 Å EMDB-17490: Rapid screening cryo-EM map of CAK bound to ICEC0942 (grid VC13-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-17491: Rapid screening cryo-EM map of CAK bound to ICEC0942 (grid VC13-2, 1hr collection) 手法: EM (単粒子) / 解像度: 4.1 Å EMDB-17492: Rapid screening cryo-EM map of CAK bound to ICEC0942 (grid VC14-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-17493: Rapid screening cryo-EM map of CAK bound to ICEC0942 (grid VC14-2, 1hr collection) 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-17494: Rapid screening cryo-EM map of CAK bound to ICEC0880 (grid VC5-1, 1hr collection) 手法: EM (単粒子) / 解像度: 3.8 Å EMDB-17495: Rapid screening cryo-EM map of CAK bound to ICEC0880 (grid VC5-2, 1hr collection) 手法: EM (単粒子) / 解像度: 3.8 Å EMDB-17496: Intermediate-resolution cryo-EM map of CAK bound to ICEC0943 (grid VC1-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-17497: Intermediate-resolution cryo-EM map of CAK bound to ICEC0768 (grid VC2-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-17498: Intermediate-resolution cryo-EM map of CAK bound to ICEC0914 (grid VC3-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-17499: Intermediate-resolution cryo-EM map of CAK bound to dinaciclib (grid VC4-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-17500: Intermediate-resolution cryo-EM map of CAK bound to ICEC0510-R (grid VC6-4, 4hr collection) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-17501: Intermediate-resolution cryo-EM map of CAK bound to ICEC0510-S (grid VC7-3, 4hr collection) 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-17502: Intermediate-resolution cryo-EM map of CAK bound to BS-181 (grid VC8-2, 4hr collection) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-17503: Intermediate-resolution cryo-EM map of CAK bound to BS-194 (grid VC9-4, 4hr collection) 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-17504: Intermediate-resolution cryo-EM map of CAK bound to ICEC0574 (grid VC11-4, 4hr collection) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-17505: Intermediate-resolution cryo-EM map of CAK bound to ICEC0829 (grid VC12-3, 4hr collection) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-17506: Intermediate-resolution cryo-EM map of CAK bound to ICEC0942 (grid VC13-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-17507: Intermediate-resolution cryo-EM map of CAK bound to ICEC0942 (grid VC14-1, 4hr collection) 手法: EM (単粒子) / 解像度: 3.2 Å 17508 8p6v EMDB-17508, PDB-8p6v: Cryo-EM structure of CAK in complex with inhibitor ICEC0942 手法: EM (単粒子) / 解像度: 1.9 Å 17509 8p6w EMDB-17509, PDB-8p6w: Cryo-EM structure of CAK in complex with inhibitor BS-181 手法: EM (単粒子) / 解像度: 1.9 Å 17510 8p6x EMDB-17510, PDB-8p6x: Cryo-EM structure of CAK in complex with inhibitor BS-194 手法: EM (単粒子) / 解像度: 1.9 Å 17511 8p6y EMDB-17511, PDB-8p6y: Cryo-EM structure of CAK in complex with nucleotide analogue ATPgS 手法: EM (単粒子) / 解像度: 1.9 Å 17512 8p6z EMDB-17512, PDB-8p6z: Cryo-EM structure of CAK in complex with inhibitor ICEC0510-R 手法: EM (単粒子) / 解像度: 2.1 Å 17513 8p70 EMDB-17513, PDB-8p70: Cryo-EM structure of CAK in complex with inhibitor ICEC0510-S 手法: EM (単粒子) / 解像度: 2.0 Å 17514 8p71 EMDB-17514, PDB-8p71: Cryo-EM structure of CAK in complex with inhibitor ICEC0574 手法: EM (単粒子) / 解像度: 2.0 Å 17515 8p72 EMDB-17515, PDB-8p72: Cryo-EM structure of CAK in complex with inhibitor ICEC0768 手法: EM (単粒子) / 解像度: 1.9 Å 17516 8p73 EMDB-17516, PDB-8p73: Cryo-EM structure of CAK in complex with inhibitor ICEC0829 手法: EM (単粒子) / 解像度: 2.0 Å 17517 8p74 EMDB-17517, PDB-8p74: Cryo-EM structure of CAK in complex with inhibitor ICEC0880 (ring-up conformation) 手法: EM (単粒子) / 解像度: 2.2 Å 17518 8p75 EMDB-17518, PDB-8p75: Cryo-EM structure of CAK in complex with inhibitor ICEC0880 (ring-down conformation) 手法: EM (単粒子) / 解像度: 2.0 Å 17519 8p76 EMDB-17519, PDB-8p76: Cryo-EM structure of CAK in complex with inhibitor ICEC0914 手法: EM (単粒子) / 解像度: 2.0 Å 17520 8p77 EMDB-17520, PDB-8p77: Cryo-EM structure of CAK in complex with inhibitor ICEC0943 手法: EM (単粒子) / 解像度: 1.8 Å 17521 8p78 EMDB-17521, PDB-8p78: Cryo-EM structure of CAK in complex with inhibitor dinaciclib 手法: EM (単粒子) / 解像度: 1.9 Å 17522 8p79 EMDB-17522, PDB-8p79: Cryo-EM structure of CAK with averaged inhibitor density 手法: EM (単粒子) / 解像度: 1.7 Å EMDB-17523: Cryo-EM structure of apo CAK 手法: EM (単粒子) / 解像度: 2.3 Å EMDB-17524: Cryo-EM map of inhibitor-bound CAK (Krios G4 performance comparison dataset) 手法: EM (単粒子) / 解像度: 2.0 Å EMDB-17525: Cryo-EM map of inhibitor-bound CAK (Glacios G2 performance comparison dataset) 手法: EM (単粒子) / 解像度: 2.3 Å EMDB-17526: Cryo-EM map of inhibitor-bound CAK (+EF performance comparison dataset) 手法: EM (単粒子) / 解像度: 2.0 Å EMDB-17527: Cryo-EM map of inhibitor-bound CAK (-EF performance comparison dataset) 手法: EM (単粒子) / 解像度: 2.4 Å 17536 8p7l EMDB-17536, PDB-8p7l: Cryo-EM structure of CDK7 subunit of CAK in complex with inhibitor LDC4297 手法: EM (単粒子) / 解像度: 2.1 Å 17754 8plz EMDB-17754, PDB-8plz: Cryo-EM structure of CAK in complex with inhibitor CT7030 手法: EM (単粒子) / 解像度: 1.9 Å
化合物	ChemComp-V0G: N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{[4-(dimethylamino)butanoyl]amino}benzamide ChemComp-HOH: WATER / 水 ChemComp-I74: (3R,4R)-4-[[[7-[(phenylmethyl)amino]-3-propan-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol 化合物画像なし ChemComp-X2H: Unknown entry ChemComp-NS9: (2S,3S)-3-{[7-(benzylamino)-3-(1-methylethyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino}butane-1,2,4-triol ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-γ-S / ATP-gamma-S, エネルギー貯蔵分子類似体YM ChemComp-MG: Unknown entry / マグネシウムジカチオン化合物画像なし ChemComp-X4L: Unknown entry 化合物画像なし ChemComp-X4Q: Unknown entry 化合物画像なし ChemComp-X4F: Unknown entry 化合物画像なし ChemComp-X2Z: Unknown entry 化合物画像なし ChemComp-X50: Unknown entry 化合物画像なし ChemComp-X58: Unknown entry 化合物画像なし ChemComp-X3Z: Unknown entry 化合物画像なし ChemComp-X1W: Unknown entry ChemComp-I73: (3S,4S)-4-[[[7-[(phenylmethyl)amino]-3-propan-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol ChemComp-1QK: 3-[({3-ethyl-5-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)methyl]-1-hydroxypyridinium / Dinaciclib 化合物画像なし ChemComp-WD9: Unknown entry 化合物画像なし ChemComp-ZQ6*: Unknown entry
由来	homo sapiens (ヒト)
キーワード	TRANSFERASE (転移酵素) / Kinase (キナーゼ) / Inhibitor / Transcription (転写 (生物学)) / Cell Cycle