+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8zcj | ||||||
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タイトル | Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex | ||||||
要素 |
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キーワード | MEMBRANE PROTEIN/IMMUNE SYSTEM / pasireotide / SSTR5 / Cryo-EM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | ||||||
機能・相同性 | 機能・相同性情報 somatostatin receptor activity / 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 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding ...somatostatin receptor activity / 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 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / neuropeptide binding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / beta2-adrenergic receptor activity / ADP signalling through P2Y purinoceptor 12 / positive regulation of mini excitatory postsynaptic potential / G alpha (q) signalling events / positive regulation of cAMP-dependent protein kinase activity / positive regulation of AMPA receptor activity / positive regulation of autophagosome maturation / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / norepinephrine binding / 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 / heat generation / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / Adrenoceptors / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / activation of transmembrane receptor protein tyrosine kinase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to glucocorticoid stimulus / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / negative regulation of smooth muscle contraction / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / positive regulation of lipophagy / G alpha (q) signalling events / photoreceptor outer segment membrane / negative regulation of multicellular organism growth / negative regulation of G protein-coupled receptor signaling pathway / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / response to psychosocial stress / endosome to lysosome transport / adrenergic receptor signaling pathway / diet induced thermogenesis / neuronal dense core vesicle / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of protein kinase A signaling / positive regulation of cytokinesis / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase binding / neuropeptide signaling pathway / smooth muscle contraction / photoreceptor outer segment / potassium channel regulator activity / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / bone resorption / positive regulation of bone mineralization / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / brown fat cell differentiation / regulation of sodium ion transport / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / cellular response to forskolin / photoreceptor inner segment / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cold / receptor-mediated endocytosis / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / Regulation of insulin secretion / G protein-coupled receptor binding 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) Rattus norvegicus (ドブネズミ) Bos taurus (ウシ) Oplophorus gracilirostris (甲殻類) synthetic construct (人工物) | ||||||
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: 3.09 Å | ||||||
データ登録者 | Li, Y.G. / Meng, X.Y. / Yang, X.R. / Ling, S.L. / Shi, P. / Tian, C.L. / Yang, F. | ||||||
資金援助 | 1件
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引用 | ジャーナル: Acta Pharmacol Sin / 年: 2024 タイトル: Structural insights into somatostatin receptor 5 bound with cyclic peptides. 著者: Ying-Ge Li / Xian-Yu Meng / Xiru Yang / Sheng-Long Ling / Pan Shi / Chang-Lin Tian / Fan Yang / 要旨: Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides ...Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/Trp of pasireotide and SSTR5. Moreover, we find that the Q, N, F and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8zcj.cif.gz | 232.7 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8zcj.ent.gz | 166.2 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8zcj.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 | 8zcj_validation.pdf.gz | 1.1 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8zcj_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | 8zcj_validation.xml.gz | 39 KB | 表示 | |
CIF形式データ | 8zcj_validation.cif.gz | 59 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/zc/8zcj ftp://data.pdbj.org/pub/pdb/validation_reports/zc/8zcj | HTTPS FTP |
-関連構造データ
関連構造データ | 39931MC 8zbeC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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 BCD
#1: タンパク質 | 分子量: 40445.059 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: GNAI1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P63096 |
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#2: タンパク質 | 分子量: 41055.867 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Rattus norvegicus (ドブネズミ) / 遺伝子: Gnb1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P54311 |
#3: 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) Bos taurus (ウシ) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P63212 |
-抗体 / タンパク質 / タンパク質・ペプチド , 3種, 3分子 EGA
#4: 抗体 | 分子量: 32724.473 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) |
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#5: タンパク質 | 分子量: 62015.930 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) Homo sapiens (ヒト), (組換発現) Oplophorus gracilirostris (甲殻類) 遺伝子: ADRB2, ADRB2R, B2AR, SSTR5 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P07550, UniProt: P35346 |
#6: タンパク質・ペプチド | 分子量: 874.016 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) synthetic construct (人工物) |
-詳細
研究の焦点であるリガンドがあるか | 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 | 名称: pasireotide-SSTR5-Gi complex / タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT | ||||||||||||||||||||
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由来(天然) |
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由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) | ||||||||||||||||||||
緩衝液 | pH: 7.5 | ||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||
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: SPOT SCAN |
電子レンズ | モード: DIFFRACTION / 最大 デフォーカス(公称値): 2000 nm / 最小 デフォーカス(公称値): 1400 nm |
撮影 | 電子線照射量: 55 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
EMソフトウェア | 名称: PHENIX / バージョン: 1.20.1_4487: / カテゴリ: モデル精密化 |
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CTF補正 | タイプ: NONE |
3次元再構成 | 解像度: 3.09 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1227503 / 対称性のタイプ: POINT |
精密化 | 交差検証法: NONE |