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基本情報
登録情報 | データベース: PDB / ID: 7rr9 | |||||||||
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タイトル | Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide bound outward open conformation | |||||||||
![]() | ATP-binding cassette sub-family D member 1 | |||||||||
![]() | TRANSPORT PROTEIN / VLCFA ABC transporter ABCD1 | |||||||||
機能・相同性 | ![]() ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / alpha-linolenic acid metabolic process / long-chain fatty acid catabolic process / long-chain fatty acid import into peroxisome ...ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / alpha-linolenic acid metabolic process / long-chain fatty acid catabolic process / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid (ALA) metabolism / regulation of fatty acid beta-oxidation / Beta-oxidation of very long chain fatty acids / Class I peroxisomal membrane protein import / very long-chain fatty acid metabolic process / sterol homeostasis / peroxisome organization / regulation of mitochondrial depolarization / fatty acyl-CoA hydrolase activity / ABC transporters in lipid homeostasis / myelin maintenance / regulation of cellular response to oxidative stress / 加水分解酵素; エステル加水分解酵素; 3価のアルコールのエステル加水分解酵素 / positive regulation of fatty acid beta-oxidation / linoleic acid metabolic process / regulation of oxidative phosphorylation / fatty acid elongation / トランスロカーゼ; 他の化合物の輸送を触媒; ヌクレオシド三リン酸の加水分解に伴う / peroxisomal membrane / long-chain fatty acid transmembrane transporter activity / fatty acid beta-oxidation / ATPase-coupled transmembrane transporter activity / negative regulation of cytokine production involved in inflammatory response / fatty acid homeostasis / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / mitochondrial membrane / ADP binding / peroxisome / protein heterodimerization activity / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / protein homodimerization activity / ATP hydrolysis activity / ATP binding / identical protein binding / membrane / cytosol / cytoplasm 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: 3.5 Å | |||||||||
![]() | Alam, A. / Le, L.T.M. / Thompson, J.R. | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment. 著者: Le Thi My Le / James Robert Thompson / Phuoc Xuan Dang / Janarjan Bhandari / Amer Alam / ![]() 要旨: The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, ...The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design. | |||||||||
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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 | ![]() | 213.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 168.7 KB | 表示 | ![]() |
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-関連構造データ
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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: 83040.867 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #2: 化合物 | 分子量: 734.039 Da / 分子数: 2 / 由来タイプ: 合成 / タイプ: SUBJECT OF INVESTIGATION #3: 化合物 | #4: 化合物 | #5: 化合物 | 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: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs / タイプ: COMPLEX 詳細: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular ...詳細: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular weight of 0.0829 MDa is for the monomer. The assembly is a homodimer. The dimer was confirmed using SEC. Entity ID: #1 / 由来: RECOMBINANT |
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分子量 | 値: 0.0829 MDa / 実験値: YES |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.5 詳細: 25mM HEPES pH 7.5, 150mM NaCl, 5mM ATP gammaS, 10mM Magnesium Chloride |
試料 | 濃度: 0.5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 |
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 90 % / 凍結前の試料温度: 277 K |
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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 / 最大 デフォーカス(公称値): 2600 nm / 最小 デフォーカス(公称値): 800 nm |
撮影 | 平均露光時間: 60 sec. / 電子線照射量: 60 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: FEI FALCON III (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.20rc3_4406: / 分類: 精密化 | ||||||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C2 (2回回転対称) | ||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 37237 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: AB INITIO MODEL / 空間: REAL | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 6JBJ Accession code: 6JBJ / Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||||||
拘束条件 |
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