+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6uun | ||||||||||||||||||
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タイトル | CryoEM Structure of the active Adrenomedullin 1 receptor G protein complex with adrenomedullin peptide | ||||||||||||||||||
要素 |
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キーワード | MEMBRANE PROTEIN / GPCR / adrenomedullin receptor complex | ||||||||||||||||||
機能・相同性 | 機能・相同性情報 adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / basement membrane assembly / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / cellular response to sucrose stimulus / adrenomedullin receptor activity / adrenomedullin receptor complex / vascular associated smooth muscle cell development ...adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / basement membrane assembly / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / cellular response to sucrose stimulus / adrenomedullin receptor activity / adrenomedullin receptor complex / vascular associated smooth muscle cell development / neuron projection regeneration / adrenomedullin receptor signaling pathway / calcitonin receptor activity / spongiotrophoblast layer development / vascular associated smooth muscle cell proliferation / calcitonin gene-related peptide receptor activity / branching involved in labyrinthine layer morphogenesis / Calcitonin-like ligand receptors / regulation of the force of heart contraction / positive regulation of vasculogenesis / regulation of systemic arterial blood pressure / bicellular tight junction assembly / developmental growth / regulation of G protein-coupled receptor signaling pathway / adherens junction assembly / G protein-coupled receptor internalization / regulation of urine volume / negative regulation of vascular permeability / sprouting angiogenesis / negative regulation of vasoconstriction / positive regulation of heart rate / odontogenesis of dentin-containing tooth / response to starvation / androgen metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cellular response to vascular endothelial growth factor stimulus / animal organ regeneration / vasculogenesis / negative regulation of endothelial cell apoptotic process / coreceptor activity / response to glucocorticoid / clathrin-coated pit / cellular response to hormone stimulus / positive regulation of vascular associated smooth muscle cell proliferation / cAMP-mediated signaling / neural tube closure / protein localization to plasma membrane / female pregnancy / G protein-coupled receptor activity / intracellular protein transport / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to insulin / Olfactory Signaling Pathway / Activation of the phototransduction cascade / hormone activity / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / receptor internalization / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / regulation of blood pressure / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / positive regulation of angiogenesis / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / calcium ion transport / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / protein transport / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / heart development / retina development in camera-type eye / Ca2+ pathway 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | Homo sapiens (ヒト) Lama glama (ラマ) | ||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3 Å | ||||||||||||||||||
データ登録者 | Belousoff, M.J. / Liang, Y.L. / Sexton, P. / Danev, R. | ||||||||||||||||||
資金援助 | オーストラリア, 日本, 5件
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引用 | ジャーナル: ACS Pharmacol Transl Sci / 年: 2020 タイトル: Structure and Dynamics of Adrenomedullin Receptors AM and AM Reveal Key Mechanisms in the Control of Receptor Phenotype by Receptor Activity-Modifying Proteins. 著者: Yi-Lynn Liang / Matthew J Belousoff / Madeleine M Fletcher / Xin Zhang / Maryam Khoshouei / Giuseppe Deganutti / Cassandra Koole / Sebastian G B Furness / Laurence J Miller / Debbie L Hay / ...著者: Yi-Lynn Liang / Matthew J Belousoff / Madeleine M Fletcher / Xin Zhang / Maryam Khoshouei / Giuseppe Deganutti / Cassandra Koole / Sebastian G B Furness / Laurence J Miller / Debbie L Hay / Arthur Christopoulos / Christopher A Reynolds / Radostin Danev / Denise Wootten / Patrick M Sexton / 要旨: Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal ...Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal lymphatic and blood vascular development and angiogenesis. They play a pivotal role in embryo implantation and fertility and can provide protection against hypoxic and oxidative stress. CGRP and AM receptors are heterodimers of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) (CGRPR), as well as RAMP2 or RAMP3 (AMR and AMR, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AMR in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AMR in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively. The structures reveal distinctions in the primary orientation of the extracellular domains (ECDs) relative to the receptor core and distinct positioning of extracellular loop 3 (ECL3) that are receptor-dependent. Analysis of dynamic data present in the cryo-EM micrographs revealed additional distinctions in the extent of mobility of the ECDs. Chimeric exchange of the linker region of the RAMPs connecting the TM helix and the ECD supports a role for this segment in controlling receptor phenotype. Moreover, a subset of the motions of the ECD appeared coordinated with motions of the G protein relative to the receptor core, suggesting that receptor ECD dynamics could influence G protein interactions. This work provides fundamental advances in our understanding of GPCR function and how this can be allosterically modulated by accessory proteins. | ||||||||||||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 6uun.cif.gz | 228.7 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6uun.ent.gz | 170.1 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 6uun.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 6uun_validation.pdf.gz | 1.3 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 6uun_full_validation.pdf.gz | 1.3 MB | 表示 | |
XML形式データ | 6uun_validation.xml.gz | 47.2 KB | 表示 | |
CIF形式データ | 6uun_validation.cif.gz | 71.4 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/uu/6uun ftp://data.pdbj.org/pub/pdb/validation_reports/uu/6uun | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#1: タンパク質 | 分子量: 45683.434 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNAS, GNAS1, GSP / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P63092 |
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#2: タンパク質 | 分子量: 38534.062 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P62873 |
#4: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P59768 |
-タンパク質 , 3種, 3分子 EPR
#3: タンパク質 | 分子量: 17839.375 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: RAMP2 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: O60895 |
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#6: タンパク質 | 分子量: 6038.813 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) Homo sapiens (ヒト) / 参照: UniProt: P35318 |
#7: タンパク質 | 分子量: 56274.520 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CALCRL, CGRPR / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: Q16602 |
-抗体 , 1種, 1分子 N
#5: 抗体 | 分子量: 15140.742 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Lama glama (ラマ) / 発現宿主: Escherichia coli (大腸菌) |
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-詳細
Has protein modification | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 |
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分子量 | 実験値: NO | ||||||||||||||||||||||||||||||
由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.4 | ||||||||||||||||||||||||||||||
試料 | 濃度: 4 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||||||||
試料支持 | 詳細: unspecified | ||||||||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 68 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.16_3549: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 111000 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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