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基本情報
登録情報 | データベース: PDB / ID: 6lz0 | ||||||
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タイトル | Cryo-EM structure of human MCT1 in complex with Basigin-2 in the presence of lactate | ||||||
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![]() | TRANSPORT PROTEIN / lactate transporter / MCT1 / Basigin-2 / Proton-coupled monocarboxylate transporter | ||||||
機能・相同性 | ![]() mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) ...mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) / succinate transmembrane transport / Proton-coupled monocarboxylate transport / pyruvate catabolic process / succinate transmembrane transporter activity / positive regulation of matrix metallopeptidase secretion / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / acrosomal membrane / response to mercury ion / organic cyclic compound binding / endothelial tube morphogenesis / neural retina development / photoreceptor cell maintenance / centrosome cycle / Basigin interactions / response to food / Aspirin ADME / odontogenesis of dentin-containing tooth / D-mannose binding / regulation of insulin secretion / decidualization / cellular response to organic cyclic compound / transport across blood-brain barrier / lateral plasma membrane / photoreceptor outer segment / positive regulation of vascular endothelial growth factor production / Integrin cell surface interactions / response to cAMP / embryo implantation / neutrophil chemotaxis / Degradation of the extracellular matrix / photoreceptor inner segment / positive regulation of endothelial cell migration / basal plasma membrane / protein localization to plasma membrane / lipid metabolic process / sarcolemma / response to peptide hormone / positive regulation of interleukin-6 production / melanosome / cell junction / glucose homeostasis / virus receptor activity / signaling receptor activity / basolateral plasma membrane / angiogenesis / positive regulation of viral entry into host cell / cell surface receptor signaling pathway / endosome / cadherin binding / apical plasma membrane / Golgi membrane / intracellular membrane-bounded organelle / focal adhesion / centrosome / synapse / endoplasmic reticulum membrane / mitochondrion / extracellular exosome / identical protein binding / membrane / plasma membrane 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
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: 3.3 Å | ||||||
![]() | Wang, N. / Jiang, X. / Zhang, S. / Zhu, A. / Yuan, Y. / Lei, J. / Yan, C. | ||||||
![]() | ![]() タイトル: Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. 著者: Nan Wang / Xin Jiang / Shuo Zhang / Angqi Zhu / Yafei Yuan / Hanwen Xu / Jianlin Lei / Chuangye Yan / ![]() ![]() 要旨: Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their ...Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs. | ||||||
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構造の表示
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 111.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 79.3 KB | 表示 | ![]() |
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 53992.852 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: P53985 |
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#2: タンパク質 | 分子量: 29254.938 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: P35613 |
#3: 化合物 | ChemComp-2OP / ( |
研究の焦点であるリガンドがあるか | Y |
-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: MCT1/Basigin-2 complex in the present of lactate / タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 8 / 詳細: 25 mM Tris pH 8.0, 150 mM NaCl, and 0.02% (w/v) GDN |
試料 | 濃度: 5 mg/ml / 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: BRIGHT FIELD / Cs: 2.7 mm |
撮影 | 電子線照射量: 37.6 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 |
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CTF補正 | タイプ: NONE | ||||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 843599 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||
精密化 | 最高解像度: 3.3 Å |