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	Structural snapshots capture nucleotide release at the μ-opioid receptor.
ジャーナル・号・ページ	Nature, Vol. 648, Issue 8094, Page 755-763, Year 2025
掲載日	2025年11月5日
著者	Saif Khan / Aaliyah S Tyson / Mohsen Ranjbar / Zixin Zhang / Jaskaran Singh / Gye Won Han / Cornelius Gati /
PubMed 要旨	As a member of the G protein-coupled receptor superfamily, the μ-opioid receptor (MOR) activates heterotrimeric G proteins by opening the Gα α-helical domain (AHD) to enable GDP-GTP exchange, ...As a member of the G protein-coupled receptor superfamily, the μ-opioid receptor (MOR) activates heterotrimeric G proteins by opening the Gα α-helical domain (AHD) to enable GDP-GTP exchange, with GDP release representing the rate-limiting step. Here, using pharmacological assays, we show that agonist efficacy correlates with decreased GDP affinity, promoting GTP exchange, whereas antagonists increase GDP affinity, dampening activation. Further investigating this phenomenon, we provide 8 unique structural models and 16 cryogenic electron microscopy maps of MOR with naloxone or loperamide, capturing several intermediate conformations along the activation pathway. These include four GDP-bound states with previously undescribed receptor-G protein interfaces, AHD arrangements and transitions in the nucleotide-binding pocket required for GDP release. Naloxone stalls MOR in a 'latent' state, whereas loperamide promotes an 'engaged' state, which is structurally poised for opening of the AHD domain and subsequent GDP release. These findings, supported by molecular dynamics simulations, identify GDP-bound intermediates and AHD conformations as key determinants of nucleotide exchange rates, providing structural and mechanistic insights into G protein activation and ligand efficacy with broad implications for G protein-coupled receptor pharmacology.
リンク	Nature / PubMed:41193810 / PubMed Central
手法	EM (単粒子)
解像度	2.73 - 8.78 Å
構造データ	EMDB-71976: Inactive-state naloxone-mu opioid receptor nanobody6 complex - Consensus map 手法: EM (単粒子) / 解像度: 3.58 Å EMDB-71977: Inactive-state naloxone-mu opioid receptor nanobody6 complex - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-71978: Inactive-state naloxone-mu opioid receptor nanobody6 complex - Locally refined fiducal map 手法: EM (単粒子) / 解像度: 3.12 Å EMDB-71979: Nucleotide-free naloxone-mu opioid receptor Gi1 complex - Consensus map 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-71980: Nucleotide-free naloxone-mu opioid receptor Gi1 complex - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-71981: Nucleotide-free naloxone-mu opioid receptor Gi1 complex - Locally refined Gi map 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-71982: Latent-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Consensus map 手法: EM (単粒子) / 解像度: 3.82 Å EMDB-71983: Latent-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.97 Å EMDB-71984: Latent-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined Gi map 手法: EM (単粒子) / 解像度: 3.15 Å EMDB-71985: Unlatched-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Consensus map 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-71986: Unlatched-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-71987: Unlatched-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined Gi map 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-71988: Primed-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Consensus map 手法: EM (単粒子) / 解像度: 3.01 Å EMDB-71989: Primed-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.05 Å EMDB-71990: Primed-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined Gi map 手法: EM (単粒子) / 解像度: 2.91 Å EMDB-71991: Engaged-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Consensus map 手法: EM (単粒子) / 解像度: 3.17 Å EMDB-71992: Engaged-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.35 Å EMDB-71993: Engaged-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined Gi map 手法: EM (単粒子) / 解像度: 2.98 Å EMDB-71998: Primed-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Consensus map 手法: EM (単粒子) / 解像度: 2.86 Å EMDB-71999: Primed-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 3.01 Å EMDB-72000: Primed-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) - Locally refined Gi GDP map 手法: EM (単粒子) / 解像度: 2.73 Å 72001 9pxu EMDB-72001, PDB-9pxu: Inactive-state naloxone-mu opioid receptor nanobody6 complex 手法: EM (単粒子) / 解像度: 3.4 Å 72002 9pxv EMDB-72002, PDB-9pxv: Nucleotide-free naloxone-mu opioid receptor Gi1 complex 手法: EM (単粒子) / 解像度: 3.02 Å 72003 9pxw EMDB-72003, PDB-9pxw: Latent-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) 手法: EM (単粒子) / 解像度: 3.8 Å 72004 9pxx EMDB-72004, PDB-9pxx: Unlatched-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) 手法: EM (単粒子) / 解像度: 3.1 Å 72005 9pxy EMDB-72005, PDB-9pxy: Primed-state naloxone-mu opioid receptor-Gi GDPbS complex (rebound) 手法: EM (単粒子) / 解像度: 3.0 Å 72006 9py2 EMDB-72006, PDB-9py2: Engaged-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) 手法: EM (単粒子) / 解像度: 3.16 Å 72008 9py4 EMDB-72008, PDB-9py4: Primed-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound) 手法: EM (単粒子) / 解像度: 2.78 Å EMDB-72022: Latent-state loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Consensus map 手法: EM (単粒子) / 解像度: 8.78 Å EMDB-72023: Latent-state loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Locally refined map 手法: EM (単粒子) / 解像度: 8.27 Å EMDB-72024: Engaged-state loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Consensus map 手法: EM (単粒子) / 解像度: 6.4 Å EMDB-72025: Engaged-state loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Locally refined map 手法: EM (単粒子) / 解像度: 4.44 Å EMDB-72026: Open-AHD loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Consensus map 手法: EM (単粒子) / 解像度: 4.24 Å EMDB-72027: Open-AHD loperamide-mu opioid receptor-Gi GDP complex (constant GDP) - Locally refined receptor map 手法: EM (単粒子) / 解像度: 4.16 Å
化合物	PDB-1apv: CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDES ChemComp-NA: Unknown entry ChemComp-CLR: CHOLESTEROL ChemComp-VSN: 5'-O-[(R)-hydroxy(thiophosphonooxy)phosphoryl]guanosine PDB-1cmv: HUMAN CYTOMEGALOVIRUS PROTEASE
由来	homo sapiens (ヒト) synthetic construct (人工物) escherichia coli (大腸菌)
キーワード	MEMBRANE PROTEIN / G protein coupled receptor / Mu Opioid receptor / Naloxone / GDP / Loperamide