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	Molecular glue CELMoD compounds are regulators of cereblon conformation.
ジャーナル・号・ページ	Science, Vol. 378, Issue 6619, Page 549-553, Year 2022
掲載日	2022年11月4日
著者	Edmond R Watson / Scott Novick / Mary E Matyskiela / Philip P Chamberlain / Andres H de la Peña / Jinyi Zhu / Eileen Tran / Patrick R Griffin / Ingrid E Wertz / Gabriel C Lander /
PubMed 要旨	Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior ...Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.
リンク	Science / PubMed:36378961 / PubMed Central
手法	EM (単粒子)
解像度	3.1 - 3.9 Å
構造データ	27012 8cvp EMDB-27012, PDB-8cvp: Cereblon-DDB1 in the Apo form 手法: EM (単粒子) / 解像度: 3.4 Å 27234 8d7u EMDB-27234, PDB-8d7u: Cereblon~DDB1 bound to CC-92480 with DDB1 in the linear conformation 手法: EM (単粒子) / 解像度: 3.1 Å 27235 8d7v EMDB-27235, PDB-8d7v: Cereblon~DDB1 bound to CC-92480 with DDB1 in the twisted conformation 手法: EM (単粒子) / 解像度: 3.2 Å 27236 8d7w EMDB-27236, PDB-8d7w: Cereblon~DDB1 bound to CC-92480 with DDB1 in the hinged conformation 手法: EM (単粒子) / 解像度: 3.1 Å 27237 8d7x EMDB-27237, PDB-8d7x: Cereblon~DDB1 in the Apo form with DDB1 in the hinged conformation 手法: EM (単粒子) / 解像度: 3.4 Å 27238 8d7y EMDB-27238, PDB-8d7y: Cereblon-DDB1 in the Apo form with DDB1 in the twisted conformation 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-27239: Cereblon bound to CC-92480, Focused Refinement 手法: EM (単粒子) / 解像度: 3.1 Å 27240 8d7z EMDB-27240, PDB-8d7z: Cereblon-DDB1 bound to CC-92480 and Ikaros ZF1-2-3 手法: EM (単粒子) / 解像度: 3.1 Å 27241 8d80 EMDB-27241, PDB-8d80: Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3 手法: EM (単粒子) / 解像度: 3.6 Å 27242 8d81 EMDB-27242, PDB-8d81: Cereblon~DDB1 bound to Pomalidomide 手法: EM (単粒子) / 解像度: 3.9 Å
化合物	ChemComp-ZN: Unknown entry ChemComp-QFC: Mezigdomide ChemComp-8W7: (3S)-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione ChemComp-Y70: S-Pomalidomide / 2-[(3S)-2,6-ジオキソ-3-ピペリジニル]-4-アミノイソインドリン-1,3-ジオン
由来	homo sapiens (ヒト)
キーワード	LIGASE / Ubiquitin / CRL4 / Adaptor / Cereblon / E3