8VMC

Composite structure of human FASN with NADPH in State 6

8VMC の概要

• エントリーDOI: 10.2210/pdb8vmc/pdb
• EMDBエントリー: 43355
• 分子名称: Fatty acid synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (2 entities in total)
• 機能のキーワード: megasynthase, lipogenesis, biosynthetic protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 560426.12

構造登録者

Schultz, K.,Marmorstein, R. (登録日: 2024-01-13, 公開日: 2025-02-26, 最終更新日: 2025-05-14)

主引用文献

Schultz, K.,Costa-Pinheiro, P.,Gardner, L.,Pinheiro, L.V.,Ramirez-Solis, J.,Gardner, S.M.,Wellen, K.E.,Marmorstein, R.
Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
Nature, 641:520-528, 2025

PubMed Abstract: 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.

PubMed: 39979457
DOI: 10.1038/s41586-025-08587-x

実験手法

ELECTRON MICROSCOPY (3.3 Å)