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データを開く
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基本情報
| 登録情報 | ![]() | |||||||||
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| タイトル | Structure of active state MC4R in complex with a potent ligand mimicking nanobody | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | GPCR / ConfoBody / agonistic nanobody / MEMBRANE PROTEIN | |||||||||
| 機能・相同性 | 機能・相同性情報regulation of eating behavior / response to melanocyte-stimulating hormone / corticotropin receptor activity / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / negative regulation of eating behavior / regulation of feeding behavior / positive regulation of bone resorption / feeding behavior / neuropeptide binding ...regulation of eating behavior / response to melanocyte-stimulating hormone / corticotropin receptor activity / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / negative regulation of eating behavior / regulation of feeding behavior / positive regulation of bone resorption / feeding behavior / neuropeptide binding / insulin secretion / response to food / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / regulation of skeletal muscle contraction / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / intracellular transport / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / cellular response to acidic pH / adenylate cyclase-activating adrenergic receptor signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / cellular response to glucagon stimulus / intracellular glucose homeostasis / Peptide ligand-binding receptors / bioluminescence / positive regulation of insulin secretion involved in cellular response to glucose stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / generation of precursor metabolites and energy / negative regulation of inflammatory response to antigenic stimulus / response to prostaglandin E / electron transport chain / response to insulin / bone development / platelet aggregation / cognition / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / positive regulation of insulin secretion / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / sensory perception of smell / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G-protein beta-subunit binding / G alpha (12/13) signalling events / positive regulation of cold-induced thermogenesis / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / G protein activity / fibroblast proliferation / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / Ras protein signal transduction / periplasmic space / electron transfer activity 類似検索 - 分子機能 | |||||||||
| 生物種 | Homo sapiens (ヒト) / ![]() Discosoma sp. (イソギンチャク) | |||||||||
| 手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.4 Å | |||||||||
データ登録者 | Busch A / Jaakola V-P / Masiulis S | |||||||||
| 資金援助 | ベルギー, 2件
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引用 | ジャーナル: Nat Commun / 年: 2024タイトル: Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist. 著者: Thomas Fontaine / Andreas Busch / Toon Laeremans / Stéphane De Cesco / Yi-Lynn Liang / Veli-Pekka Jaakola / Zara Sands / Sarah Triest / Simonas Masiulis / Lies Dekeyzer / Noor Samyn / ...著者: Thomas Fontaine / Andreas Busch / Toon Laeremans / Stéphane De Cesco / Yi-Lynn Liang / Veli-Pekka Jaakola / Zara Sands / Sarah Triest / Simonas Masiulis / Lies Dekeyzer / Noor Samyn / Nicolas Loeys / Lisa Perneel / Melanie Debaere / Murielle Martini / Charlotte Vantieghem / Richa Virmani / Kamila Skieterska / Stephanie Staelens / Rosa Barroco / Maarten Van Roy / Christel Menet / ![]() 要旨: The melanocortin receptor 4 (MC4R) belongs to the melanocortin receptor family of G-protein coupled receptors and is a key switch in the leptin-melanocortin molecular axis that controls hunger and ...The melanocortin receptor 4 (MC4R) belongs to the melanocortin receptor family of G-protein coupled receptors and is a key switch in the leptin-melanocortin molecular axis that controls hunger and satiety. Brain-produced hormones such as α-melanocyte-stimulating hormone (agonist) and agouti-related peptide (inverse agonist) regulate the molecular communication of the MC4R axis but are promiscuous for melanocortin receptor subtypes and induce a wide array of biological effects. Here, we use a chimeric construct of conformation-selective, nanobody-based binding domain (a ConfoBody Cb80) and active state-stabilized MC4R-β2AR hybrid for efficient de novo discovery of a sequence diverse panel of MC4R-specific, potent and full agonistic nanobodies. We solve the active state MC4R structure in complex with the full agonistic nanobody pN162 at 3.4 Å resolution. The structure shows a distinct interaction with pN162 binding deeply in the orthosteric pocket. MC4R peptide agonists, such as the marketed setmelanotide, lack receptor selectivity and show off-target effects. In contrast, the agonistic nanobody is highly specific and hence can be a more suitable agent for anti-obesity therapeutic intervention via MC4R. | |||||||||
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構造の表示
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ダウンロードとリンク
-EMDBアーカイブ
| マップデータ | emd_18442.map.gz | 19.8 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-18442-v30.xml emd-18442.xml | 23.8 KB 23.8 KB | 表示 表示 | EMDBヘッダ |
| FSC (解像度算出) | emd_18442_fsc.xml | 8.7 KB | 表示 | FSCデータファイル |
| 画像 | emd_18442.png | 35.6 KB | ||
| マスクデータ | emd_18442_msk_1.map | 22.2 MB | マスクマップ | |
| Filedesc metadata | emd-18442.cif.gz | 7.6 KB | ||
| その他 | emd_18442_half_map_1.map.gz emd_18442_half_map_2.map.gz | 20.6 MB 20.6 MB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-18442 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-18442 | HTTPS FTP |
-関連構造データ
| 関連構造データ | ![]() 8qj2MC M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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| 類似構造データ | 類似検索 - 機能・相同性 F&H 検索 |
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リンク
| EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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| 「今月の分子」の関連する項目 |
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マップ
| ファイル | ダウンロード / ファイル: emd_18442.map.gz / 形式: CCP4 / 大きさ: 22.2 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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| 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: 1.425 Å | ||||||||||||||||||||||||||||||||||||
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| 対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
| 詳細 | EMDB XML:
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-添付データ
-マスク #1
| ファイル | emd_18442_msk_1.map | ||||||||||||
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| 密度ヒストグラム |
-ハーフマップ: #2
| ファイル | emd_18442_half_map_1.map | ||||||||||||
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| 投影像・断面図 |
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| 密度ヒストグラム |
-ハーフマップ: #1
| ファイル | emd_18442_half_map_2.map | ||||||||||||
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| 投影像・断面図 |
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試料の構成要素
-全体 : MC4R receptor in complex with Gs protein heterotrimer, nanobody-3...
| 全体 | 名称: MC4R receptor in complex with Gs protein heterotrimer, nanobody-35/ConfoBody 35 and ligand-mimicking nanobody |
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| 要素 |
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-超分子 #1: MC4R receptor in complex with Gs protein heterotrimer, nanobody-3...
| 超分子 | 名称: MC4R receptor in complex with Gs protein heterotrimer, nanobody-35/ConfoBody 35 and ligand-mimicking nanobody タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
| 分子 | 名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 1 / 詳細: Dominant-negative / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 45.699434 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 SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCS VDTENIRRVF NDCRDIIQRM HLRQYELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-分子 #2: 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: 2 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 38.534062 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...文字列: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: 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: 3 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 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 UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #4: Nanobody-35
| 分子 | 名称: Nanobody-35 / タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: ![]() |
| 分子量 | 理論値: 15.140742 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHHEPEA |
-分子 #5: Soluble cytochrome b562,Melanocortin receptor 4,Red fluorescent p...
| 分子 | 名称: Soluble cytochrome b562,Melanocortin receptor 4,Red fluorescent protein drFP583 タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Discosoma sp. (イソギンチャク) |
| 分子量 | 理論値: 82.025141 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: FADYKDDDDK AADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLLE VLFQGPMVNS THRGMHTSLH LWNRSSYRLH SNASESLGKG Y SDGGCYEQ ...文字列: FADYKDDDDK AADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLLE VLFQGPMVNS THRGMHTSLH LWNRSSYRLH SNASESLGKG Y SDGGCYEQ LFVSPEVFVT LGVISLLENI LVIVAIAKNK NLHSPMYFFI CSLAVADMLV SVSNGSETIV ITLLNSTDTD AQ SFTVNID NVIDSVICSS LLASICSLLS IAVDRYFTIF YALQYHNIMT VKRVGIIISC IWAACTVSGI LFIIYSDSSA VII CLITMF FTMLALMASL YVHMFLMARL HIKRIAVLPG TGAIRQGANM KGAITLTILI GVFVVCWAPF FLHLIFYISC PQNP YCVCF MSHFNLYLIL IMCNSIIDPL IYALRSQELR KTFKEIICCY PLGGLCDLSS RYLEVLFQGP VSKGEEDNMA IIKEF MRFK VHMEGSVNGH EFEIEGEGEG RPYEGTQTAK LKVTKGGPLP FAWDILSPQF MYGSKAYVKH PADIPDYLKL SFPEGF KWE RVMNFEDGGV VTVTQDSSLQ DGEFIYKVKL RGTNFPSDGP VMQKKTMGWE ASSERMYPED GALKGEIKQR LKLKDGG HY DAEVKTTYKA KKPVQLPGAY NVNIKLDITS HNEDYTIVEQ YERAEGRHST GGMDELYKHH HHHHHHHHGL NDIFEAQK I EWHEEPEA UniProtKB: Soluble cytochrome b562, Melanocortin receptor 4, Red fluorescent protein drFP583 |
-分子 #6: pN162
| 分子 | 名称: pN162 / タイプ: protein_or_peptide / ID: 6 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: ![]() |
| 分子量 | 理論値: 12.655162 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: QVQLVESGGG LVQPGGSLRL SCAASGSAFS LNVMGWYRQT PGNQRALVAE ITKDGSTNYA DSAKGRFTIS RDNAKNTVHL QMDSLKPED TAVYYCKART GRIVRPLDYW GQGTQVTV |
-実験情報
-構造解析
| 手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
| 試料の集合状態 | particle |
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試料調製
| 濃度 | 10.4 mg/mL |
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| 緩衝液 | pH: 7.4 |
| 凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV |
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電子顕微鏡法
| 顕微鏡 | TFS GLACIOS |
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| 撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 30.3 e/Å2 |
| 電子線 | 加速電圧: 200 kV / 電子線源: FIELD EMISSION GUN |
| 電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.5 µm / 最小 デフォーカス(公称値): 0.5 µm |
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万見について




キーワード
Homo sapiens (ヒト)
Discosoma sp. (イソギンチャク)
データ登録者
ベルギー, 2件
引用






























Z (Sec.)
Y (Row.)
X (Col.)












































Trichoplusia ni (イラクサキンウワバ)
解析
FIELD EMISSION GUN
