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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
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Structure paper

タイトル	Time-resolved cryo-EM of G-protein activation by a GPCR.
ジャーナル・号・ページ	Nature, Vol. 629, Issue 8014, Page 1182-1191, Year 2024
掲載日	2024年3月13日
著者	Makaía M Papasergi-Scott / Guillermo Pérez-Hernández / Hossein Batebi / Yang Gao / Gözde Eskici / Alpay B Seven / Ouliana Panova / Daniel Hilger / Marina Casiraghi / Feng He / Luis Maul / Peter Gmeiner / Brian K Kobilka / Peter W Hildebrand / Georgios Skiniotis /
PubMed 要旨	G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit. To visualize this mechanism, we developed a time-resolved cryo-EM ...G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit. To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G-protein complex. By monitoring the transitions of the stimulatory G protein in complex with the β-adrenergic receptor at short sequential time points after GTP addition, we identified the conformational trajectory underlying G-protein activation and functional dissociation from the receptor. Twenty structures generated from sequential overlapping particle subsets along this trajectory, compared to control structures, provide a high-resolution description of the order of main events driving G-protein activation in response to GTP binding. Structural changes propagate from the nucleotide-binding pocket and extend through the GTPase domain, enacting alterations to Gα switch regions and the α5 helix that weaken the G-protein-receptor interface. Molecular dynamics simulations with late structures in the cryo-EM trajectory support that enhanced ordering of GTP on closure of the α-helical domain against the nucleotide-bound Ras-homology domain correlates with α5 helix destabilization and eventual dissociation of the G protein from the GPCR. These findings also highlight the potential of time-resolved cryo-EM as a tool for mechanistic dissection of GPCR signalling events.
リンク	Nature / PubMed:38480881
手法	EM (単粒子)
解像度	2.9 - 4.2 Å
構造データ	29951 8gdz EMDB-29951, PDB-8gdz: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#1 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 29952 8ge1 EMDB-29952, PDB-8ge1: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#2 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 29953 8ge2 EMDB-29953, PDB-8ge2: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#3 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29954 8ge3 EMDB-29954, PDB-8ge3: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#4 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29955 8ge4 EMDB-29955, PDB-8ge4: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#5 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29956 8ge5 EMDB-29956, PDB-8ge5: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#6 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 29958 8ge6 EMDB-29958, PDB-8ge6: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#7 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 29959 8ge7 EMDB-29959, PDB-8ge7: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#8 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 29960 8ge8 EMDB-29960, PDB-8ge8: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#9 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 29961 8ge9 EMDB-29961, PDB-8ge9: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#10 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 29962 8gea EMDB-29962, PDB-8gea: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#11 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 29964 8geb EMDB-29964, PDB-8geb: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#12 of 20) 手法: EM (単粒子) / 解像度: 3.6 Å 29965 8gec EMDB-29965, PDB-8gec: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#13 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 29966 8ged EMDB-29966, PDB-8ged: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#14 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 29967 8gee EMDB-29967, PDB-8gee: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#15 of 20) 手法: EM (単粒子) / 解像度: 3.7 Å 29968 8gef EMDB-29968, PDB-8gef: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#16 of 20) 手法: EM (単粒子) / 解像度: 3.8 Å 29969 8geg EMDB-29969, PDB-8geg: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#17 of 20) 手法: EM (単粒子) / 解像度: 3.8 Å 29970 8geh EMDB-29970, PDB-8geh: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#18 of 20) 手法: EM (単粒子) / 解像度: 4.0 Å 29971 8gei EMDB-29971, PDB-8gei: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#19 of 20) 手法: EM (単粒子) / 解像度: 4.1 Å 29972 8gej EMDB-29972, PDB-8gej: CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#20 of 20) 手法: EM (単粒子) / 解像度: 4.2 Å 29985 8gfv EMDB-29985, PDB-8gfv: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #1 of 20) 手法: EM (単粒子) / 解像度: 3.1 Å 29986 8gfw EMDB-29986, PDB-8gfw: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #2 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29987 8gfx EMDB-29987, PDB-8gfx: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #3 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29988 8gfy EMDB-29988, PDB-8gfy: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #4 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29989 8gfz EMDB-29989, PDB-8gfz: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #5 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29990 8gg0 EMDB-29990, PDB-8gg0: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #6 of 20) 手法: EM (単粒子) / 解像度: 2.9 Å 29991 8gg1 EMDB-29991, PDB-8gg1: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #7 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29992 8gg2 EMDB-29992, PDB-8gg2: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #8 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å 29993 8gg3 EMDB-29993, PDB-8gg3: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #9 of 20) 手法: EM (単粒子) / 解像度: 3.1 Å 29994 8gg4 EMDB-29994, PDB-8gg4: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #10 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 29995 8gg5 EMDB-29995, PDB-8gg5: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #11 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 29996 8gg6 EMDB-29996, PDB-8gg6: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #12 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29997 8gg7 EMDB-29997, PDB-8gg7: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #13 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29998 8gg8 EMDB-29998, PDB-8gg8: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #14 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 29999 8gg9 EMDB-29999, PDB-8gg9: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #15 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 40000 8gga EMDB-40000, PDB-8gga: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #16 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40001 8ggb EMDB-40001, PDB-8ggb: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #17 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40002 8ggc EMDB-40002, PDB-8ggc: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #18 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 40004 8gge EMDB-40004, PDB-8gge: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #19 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40005 8ggf EMDB-40005, PDB-8ggf: CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #20 of 20) 手法: EM (単粒子) / 解像度: 3.6 Å 40009 8ggi EMDB-40009, PDB-8ggi: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #1 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40010 8ggj EMDB-40010, PDB-8ggj: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #2 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40011 8ggk EMDB-40011, PDB-8ggk: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #3 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 40012 8ggl EMDB-40012, PDB-8ggl: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #4 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 40013 8ggm EMDB-40013, PDB-8ggm: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #5 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 40014 8ggn EMDB-40014, PDB-8ggn: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #6 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å 40015 8ggo EMDB-40015, PDB-8ggo: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #7 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 40016 8ggp EMDB-40016, PDB-8ggp: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #8 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å 40017 8ggq EMDB-40017, PDB-8ggq: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #9 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 40018 8ggr EMDB-40018, PDB-8ggr: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #10 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 40019 8ggs EMDB-40019, PDB-8ggs: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #11 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40020 8ggt EMDB-40020, PDB-8ggt: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #12 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40021 8ggu EMDB-40021, PDB-8ggu: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #13 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å 40022 8ggv EMDB-40022, PDB-8ggv: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #14 of 20) 手法: EM (単粒子) / 解像度: 3.5 Å 40023 8ggw EMDB-40023, PDB-8ggw: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #15 of 20) 手法: EM (単粒子) / 解像度: 3.6 Å 40024 8ggx EMDB-40024, PDB-8ggx: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #16 of 20) 手法: EM (単粒子) / 解像度: 3.6 Å 40025 8ggy EMDB-40025, PDB-8ggy: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #17 of 20) 手法: EM (単粒子) / 解像度: 3.9 Å 40026 8ggz EMDB-40026, PDB-8ggz: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #18 of 20) 手法: EM (単粒子) / 解像度: 3.9 Å 40027 8gh0 EMDB-40027, PDB-8gh0: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #19 of 20) 手法: EM (単粒子) / 解像度: 4.0 Å 40028 8gh1 EMDB-40028, PDB-8gh1: Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #20 of 20) 手法: EM (単粒子) / 解像度: 4.1 Å EMDB-40096: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#1 of 20) 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-40097: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#2 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-40098: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#3 of 20) 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-40099: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#4 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-40100: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#5 of 20) 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-40101: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#6 of 20) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-40102: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#7 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-40103: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#8 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-40104: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#9 of 20) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-40105: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#10 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-40106: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#11 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-40107: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#12 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-40108: CryoEM structure of beta-2-adrenergic receptor in complex with Gs heterotrimer, 5 sec after GTP addition (#13 of 20) 手法: EM (単粒子) / 解像度: 3.0 Å