+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-13453 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
タイトル | Cryo-EM structure of the agonist setmelanotide bound to the active melanocortin-4 receptor (MC4R) in complex with the heterotrimeric Gs protein at 2.6 A resolution. | ||||||||||||
マップデータ | |||||||||||||
試料 |
| ||||||||||||
機能・相同性 | 機能・相同性情報 regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor ...regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of metabolic process / feeding behavior / neuropeptide binding / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / G alpha (i) signalling events / insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / alkylglycerophosphoethanolamine phosphodiesterase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of feeding behavior / diet induced thermogenesis / PKA activation in glucagon signalling / peptide hormone binding / hair follicle placode formation / developmental growth / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / positive regulation of bone resorption / renal water homeostasis / Hedgehog 'off' state / Transcriptional and post-translational regulation of MITF-M expression and activity / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / cellular response to glucagon stimulus / adenylate cyclase activator activity / regulation of insulin secretion / photoreceptor inner segment / Peptide ligand-binding receptors / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein activity / platelet aggregation / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) / synthetic construct (人工物) / Rattus norvegicus (ドブネズミ) / Bos taurus (ウシ) / Lama glama (ラマ) | ||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.58 Å | ||||||||||||
データ登録者 | Heyder NA / Schmidt A / Kleinau G / Hilal T / Scheerer P | ||||||||||||
資金援助 | ドイツ, 3件
| ||||||||||||
引用 | ジャーナル: Cell Res / 年: 2021 タイトル: Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide. 著者: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / ...著者: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / Thorsten Mielke / Annette G Beck-Sickinger / Peter W Hildebrand / Christian M T Spahn / Daniel Hilger / Magdalena Schacherl / Heike Biebermann / Tarek Hilal / Peter Kühnen / Brian K Kobilka / Patrick Scheerer / 要旨: The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of ...The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs. | ||||||||||||
履歴 |
|
-構造の表示
ムービー |
ムービービューア |
---|---|
構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_13453.map.gz | 10 MB | EMDBマップデータ形式 | |
---|---|---|---|---|
ヘッダ (付随情報) | emd-13453-v30.xml emd-13453.xml | 24.8 KB 24.8 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_13453_fsc.xml | 9.7 KB | 表示 | FSCデータファイル |
画像 | emd_13453.png | 118.1 KB | ||
その他 | emd_13453_additional_1.map.gz | 17.5 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-13453 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13453 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_13453_validation.pdf.gz | 340.1 KB | 表示 | EMDB検証レポート |
---|---|---|---|---|
文書・詳細版 | emd_13453_full_validation.pdf.gz | 339.7 KB | 表示 | |
XML形式データ | emd_13453_validation.xml.gz | 11.3 KB | 表示 | |
CIF形式データ | emd_13453_validation.cif.gz | 14.8 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13453 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13453 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
---|---|
「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_13453.map.gz / 形式: CCP4 / 大きさ: 83.7 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.832 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
|
-添付データ
-追加マップ: #1
ファイル | emd_13453_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-試料の構成要素
-全体 : Ternary complex of setmelanotide-activated melanocortin 4 recepto...
全体 | 名称: Ternary complex of setmelanotide-activated melanocortin 4 receptor with heterotrimeric Gs, further stabilized by addition of nanobody 35 |
---|---|
要素 |
|
-超分子 #1: Ternary complex of setmelanotide-activated melanocortin 4 recepto...
超分子 | 名称: Ternary complex of setmelanotide-activated melanocortin 4 receptor with heterotrimeric Gs, further stabilized by addition of nanobody 35 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6 |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 実験値: 144.1 kDa/nm |
-分子 #1: Melanocortin receptor 4
分子 | 名称: Melanocortin receptor 4 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 38.69852 KDa |
組換発現 | 生物種: Spodoptera aff. frugiperda 1 BOLD-2017 (蝶・蛾) |
配列 | 文字列: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI ...文字列: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI MTVKRVGIII SCIWAACTVS GILFIIYSDS SAVIICLITM FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GT GAIRQGA NMKGAITLTI LIGVFVVCWA PFFLHLIFYI SCPQNPYCVC FMSHFNLYLI LIMCNSIIDP LIYALRSQEL RKT FKEIIC CYPLGGLCDL SSRYLEVLFQ |
-分子 #2: Setmelanotide (other names RM-493; BIM-22493; IRC-022493; Imcivree)
分子 | 名称: Setmelanotide (other names RM-493; BIM-22493; IRC-022493; Imcivree) タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: synthetic construct (人工物) |
分子量 | 理論値: 1.081297 KDa |
配列 | 文字列: RC(DAL)H(DPN)RWC |
-分子 #3: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...
分子 | 名称: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 44.32616 KDa |
組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
配列 | 文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI ...文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI DVIKQADYVP SDQDLLRCRV LTSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVASSS YN MVIREDN QTNRLQEALN LFKSIWNNRW LRTISVILFL NKQDLLAEKV LAGKSKIEDY FPEFARYTTP EDATPEPGED PRV TRAKYF IRDEFLRIST ASGDGRHYCY PHFTCAVDTE NIRRVFNDCR DIIQRMHLRQ YELL |
-分子 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Rattus norvegicus (ドブネズミ) |
分子量 | 理論値: 37.728152 KDa |
組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
配列 | 文字列: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...文字列: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN |
-分子 #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Bos taurus (ウシ) |
分子量 | 理論値: 7.861143 KDa |
組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-分子 #6: Camelid antibody fragment - nanobody 35
分子 | 名称: Camelid antibody fragment - nanobody 35 / タイプ: protein_or_peptide / ID: 6 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Lama glama (ラマ) |
分子量 | 理論値: 14.71432 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHH |
-分子 #7: CALCIUM ION
分子 | 名称: CALCIUM ION / タイプ: ligand / ID: 7 / コピー数: 1 / 式: CA |
---|---|
分子量 | 理論値: 40.078 Da |
-分子 #8: water
分子 | 名称: water / タイプ: ligand / ID: 8 / コピー数: 88 / 式: HOH |
---|---|
分子量 | 理論値: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
---|---|
解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 5 mg/mL | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
緩衝液 | pH: 7.5 構成要素:
| ||||||||||||||||||||||||
グリッド | モデル: UltrAuFoil R1.2/1.3 / 材質: GOLD / 前処理 - タイプ: GLOW DISCHARGE | ||||||||||||||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 283.15 K / 装置: FEI VITROBOT MARK IV |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
---|---|
撮影 | フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 検出モード: COUNTING / 撮影したグリッド数: 1 / 実像数: 7583 / 平均露光時間: 40.78 sec. / 平均電子線量: 40.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | C2レンズ絞り径: 50.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm / 最大 デフォーカス(公称値): 2.0 µm / 最小 デフォーカス(公称値): 0.8 µm / 倍率(公称値): 96000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |