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基本情報
登録情報 | データベース: PDB / ID: 8zbe | ||||||
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タイトル | cryo-EM structure of the octreotide-bound SSTR5-Gi complex | ||||||
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![]() | MEMBRANE PROTEIN/IMMUNE SYSTEM / SSTR5 / octreoitde / structural protein / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | ||||||
機能・相同性 | ![]() 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / neuropeptide binding ...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 / 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 / Ca2+ pathway / 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 / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / : / beta2-adrenergic receptor activity / positive regulation of mini excitatory postsynaptic potential / G alpha (i) signalling events / positive regulation of cAMP-dependent protein kinase activity / Thrombin signalling through proteinase activated receptors (PARs) / cellular response to glucocorticoid stimulus / norepinephrine binding / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / photoreceptor outer segment membrane / response to psychosocial stress / negative regulation of multicellular organism growth / spectrin binding / adrenergic receptor signaling pathway / endosome to lysosome transport / diet induced thermogenesis / neuronal dense core vesicle / 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 / smooth muscle contraction / photoreceptor outer segment / potassium channel regulator activity / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / positive regulation of bone mineralization / G protein-coupled serotonin receptor binding / brown fat cell differentiation / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / regulation of mitotic spindle organization / cellular response to forskolin / bone resorption / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cold / photoreceptor inner segment / Peptide ligand-binding receptors / receptor-mediated endocytosis / Regulation of insulin secretion / G protein-coupled receptor binding / clathrin-coated endocytic vesicle membrane / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of protein serine/threonine kinase activity / ADP signalling through P2Y purinoceptor 12 / response to peptide hormone / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / cellular response to amyloid-beta / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / Cargo recognition for clathrin-mediated endocytosis / GTPase binding / retina development in camera-type eye / Clathrin-mediated endocytosis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / amyloid-beta binding / cell cortex / midbody / G alpha (i) signalling events 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() ![]() 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: 3.24 Å | ||||||
![]() | 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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![]() | ![]() 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. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 224.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 159.8 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 1.1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.1 MB | 表示 | |
XML形式データ | ![]() | 38.8 KB | 表示 | |
CIF形式データ | ![]() | 58.3 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 39901 ![]() 39931 ![]() 8zcjC 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 BDC
#2: 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) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P63096 |
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#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) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: A0A9X9ZA26 |
#6: 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) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: P54311 |
-タンパク質 / 抗体 / タンパク質・ペプチド , 3種, 3分子 AEP
#1: 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) ![]() ![]() 遺伝子: ADRB2, ADRB2R, B2AR, SSTR5 発現宿主: ![]() ![]() 参照: UniProt: P07550, UniProt: P35346 |
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#4: 抗体 | 分子量: 32708.473 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() |
#5: タンパク質・ペプチド | 分子量: 1036.246 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 |
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試料調製
構成要素 | 名称: octreotide-bound 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: ![]() ![]() | ||||||||||||||||||||
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 |
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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: ![]() |
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) |
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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: 3.24 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 452725 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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