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 mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.
ジャーナル・号・ページ	Nat Chem Biol, Vol. 21, Issue 7, Page 1046-1057, Year 2025
掲載日	2025年1月7日
著者	Aaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry Kenakin / Ryan Shenvi / Susruta Majumdar / Cornelius Gati /
PubMed 要旨	Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex ...Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-G protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-G protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR-G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free 'inactive' receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology.
リンク	Nat Chem Biol / PubMed:39775170 / PubMed Central
手法	EM (単粒子)
解像度	3.0 - 3.58 Å
構造データ	43556 8vve EMDB-43556, PDB-8vve: Kappa opioid receptor:Galphai protein in complex with inverse agonist norBNI 手法: EM (単粒子) / 解像度: 3.3 Å 43557 8vvf EMDB-43557, PDB-8vvf: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic 手法: EM (単粒子) / 解像度: 3.0 Å 43558 8vvg EMDB-43558, PDB-8vvg: Kappa opioid receptor in complex with heterotrimerig Gi protein, bound to inverse agonist GB18 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43648: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic, Original map receptor 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-43649: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic, Original map G protein 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-43652: Kappa opioid receptor:Galphai protein in complex with inverse agonist norBNI, Original map G protein 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43653: Kappa opioid receptor:Galphai protein in complex with inverse agonist GB18, Original map receptor 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43654: Kappa opioid receptor:Galphai protein in complex with inverse agonist GB18, Original map G protein 手法: EM (単粒子) / 解像度: 3.3 Å 46585 9d61 EMDB-46585, PDB-9d61: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic , no scFv16 手法: EM (単粒子) / 解像度: 3.58 Å
化合物	PDB-1ad6: DOMAIN A OF HUMAN RETINOBLASTOMA TUMOR SUPPRESSOR ChemComp-JDC: (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide / アンタゴニストYM PDB-1ad5*: SRC FAMILY KINASE HCK-AMP-PNP COMPLEX
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	MEMBRANE PROTEIN / G protein coupled receptor / Opioid receptor