EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.
ジャーナル・号・ページ	Cell, Vol. 184, Issue 2, Page 370-383.e13, Year 2021
掲載日	2021年1月21日
著者	Nan Wang / Xin Jiang / Shuo Zhang / Angqi Zhu / Yafei Yuan / Hanwen Xu / Jianlin Lei / Chuangye Yan /
PubMed 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.
リンク	Cell / PubMed:33333023
手法	EM (単粒子)
解像度	2.95 - 3.3 Å
構造データ	30019 6lyy EMDB-30019, PDB-6lyy: Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate AZD3965 in the outward-open conformation. 手法: EM (単粒子) / 解像度: 3.2 Å 30020 6lz0 EMDB-30020, PDB-6lz0: Cryo-EM structure of human MCT1 in complex with Basigin-2 in the presence of lactate 手法: EM (単粒子) / 解像度: 3.3 Å 30389 7cko EMDB-30389: Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate 7ACC2 in the inward-open conformation. PDB-7cko: Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate 7ACC2 in the inward-open conformation 手法: EM (単粒子) / 解像度: 2.95 Å 30391 7ckr EMDB-30391, PDB-7ckr: Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate BAY-8002 in the outward-open conformation. 手法: EM (単粒子) / 解像度: 3.0 Å 30623 7da5 EMDB-30623, PDB-7da5: Cryo-EM structure of the human MCT1 D309N mutant in complex with Basigin-2 in the inward-open conformation. 手法: EM (単粒子) / 解像度: 3.3 Å
化合物	ChemComp-EY0: 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione ChemComp-2OP: (2S)-2-HYDROXYPROPANOIC ACID / L-乳酸 ChemComp-G5L: 7-[methyl-(phenylmethyl)amino]-2-oxidanylidene-chromene-3-carboxylic acid / 2-オキソ-7-(メチルベンジルアミノ)-2H-1-ベンゾピラン-3-カルボン酸 ChemComp-G5O: 2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN / Proton-coupled monocarboxylate transporter / MCT1 / Basigin / anti-cancer / AZD3965 / BAY-8002 / 7ACC2 / single particle cryo-EM / latate transporter / lactate transporter / Basigin-2 / anti-cancer drug candidate