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	Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
ジャーナル・号・ページ	Nature, Vol. 641, Issue 8062, Page 520-528, Year 2025
掲載日	2025年2月20日
著者	Kollin Schultz / Pedro Costa-Pinheiro / Lauren Gardner / Laura V Pinheiro / Julio Ramirez-Solis / Sarah M Gardner / Kathryn E Wellen / Ronen Marmorstein /
PubMed 要旨	The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly ...The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP-DH and ACP-ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.
リンク	Nature / PubMed:39979457 / PubMed Central
手法	EM (単粒子)
解像度	3.11 - 3.66 Å
構造データ	43187 8vf7 EMDB-43187, PDB-8vf7: Modifying portion of human FASN with NADPH and the ACP at the ER domain 手法: EM (単粒子) / 解像度: 3.2 Å 43199 8vg4 EMDB-43199, PDB-8vg4: Modifying portion of human FASN with NADPH and the ACP at the DH domain 手法: EM (単粒子) / 解像度: 3.11 Å 43337 8vle EMDB-43337, PDB-8vle: Composite structure of human FASN with NADPH in State 1 手法: EM (単粒子) / 解像度: 3.3 Å 43340 8vlo EMDB-43340, PDB-8vlo: Composite structure of human FASN with NADPH in State 2 手法: EM (単粒子) / 解像度: 3.3 Å 43341 8vlp EMDB-43341, PDB-8vlp: Composite structure of human FASN with NADPH in State 3 手法: EM (単粒子) / 解像度: 3.2 Å 43350 8vm0 EMDB-43350, PDB-8vm0: Composite structure of human FASN with NADPH in State 4 手法: EM (単粒子) / 解像度: 3.3 Å 43352 8vm5 EMDB-43352, PDB-8vm5: Composite structure of human FASN with NADPH in State 5 手法: EM (単粒子) / 解像度: 3.3 Å 43353 8vm6 EMDB-43353, PDB-8vm6: Composite structure of human FASN with NADPH in State 8 手法: EM (単粒子) / 解像度: 3.5 Å 43354 8vm7 EMDB-43354, PDB-8vm7: Composite structure of human FASN with NADPH in State 7 手法: EM (単粒子) / 解像度: 3.3 Å 43355 8vmc EMDB-43355, PDB-8vmc: Composite structure of human FASN with NADPH in State 6 手法: EM (単粒子) / 解像度: 3.3 Å 43356 8vmd EMDB-43356, PDB-8vmd: Modifying portion of human FASN with NADP+ and the ACP at the DH domain 手法: EM (単粒子) / 解像度: 3.46 Å EMDB-43414: Consensus map of hFASN/NADPH State 1 手法: EM (単粒子) / 解像度: 3.63 Å EMDB-43415: Focused map of the modifying region of hFASN/NADPH State 1 手法: EM (単粒子) / 解像度: 3.31 Å EMDB-43417: Focused map of the condensing region of hFASN/NADPH State 1 手法: EM (単粒子) / 解像度: 3.27 Å EMDB-43441: Consensus map of hFASN/NADPH State 5 手法: EM (単粒子) / 解像度: 3.29 Å EMDB-43442: Focused map of the modifying region of hFASN/NADPH State 5 手法: EM (単粒子) / 解像度: 3.23 Å EMDB-43445: Focused map of the condensing region of hFASN/NADPH State 5 手法: EM (単粒子) / 解像度: 3.44 Å EMDB-43447: Consensus map of hFASN/NADPH State 3 手法: EM (単粒子) / 解像度: 3.35 Å EMDB-43448: Focused map of the modifying region of hFASN/NADPH State 3 手法: EM (単粒子) / 解像度: 3.22 Å EMDB-43449: Focused map of the condensing region of hFASN/NADPH State 3 手法: EM (単粒子) / 解像度: 3.18 Å EMDB-43454: Consensus map of hFASN/NADPH State 7 手法: EM (単粒子) / 解像度: 3.45 Å EMDB-43456: Focused map of the modifying region of hFASN/NADPH State 7 手法: EM (単粒子) / 解像度: 3.28 Å EMDB-43457: Focused map of the condensing region of hFASN/NADPH State 7 手法: EM (単粒子) / 解像度: 3.27 Å EMDB-43458: Consensus map of hFASN/NADPH State 2 手法: EM (単粒子) / 解像度: 3.65 Å EMDB-43459: Focused map of the modifying region of hFASN/NADPH State 2 手法: EM (単粒子) / 解像度: 3.32 Å EMDB-43465: Focused map of the condensing region of hFASN/NADPH State 2 手法: EM (単粒子) / 解像度: 3.22 Å EMDB-43466: Consensus map of hFASN/NADPH State 4 手法: EM (単粒子) / 解像度: 3.58 Å EMDB-43467: Focused map of the modifying region of hFASN/NADPH State 4 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43468: Focused map of the condensing region of hFASN/NADPH State 4 手法: EM (単粒子) / 解像度: 3.29 Å EMDB-43469: Consensus map of hFASN/NADPH State 6 手法: EM (単粒子) / 解像度: 3.28 Å EMDB-43470: Focused map of the modifying region of hFASN/NADPH State 6 手法: EM (単粒子) / 解像度: 3.19 Å EMDB-43471: Focused map of the condensing region of hFASN/NADPH State 6 手法: EM (単粒子) / 解像度: 3.31 Å EMDB-43472: Consensus map of hFASN/NADPH State 8 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-43473: Focused map of the modifying region of hFASN/NADPH State 8 手法: EM (単粒子) / 解像度: 3.36 Å EMDB-43474: Focus map of the condensing region of hFASN/NADPH State 8 手法: EM (単粒子) / 解像度: 3.66 Å
化合物	ChemComp-NDP: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / NADPH ChemComp-NAP: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
由来	homo sapiens (ヒト)
キーワード	BIOSYNTHETIC PROTEIN / Megasynthase / Lipogenesis