8VLE
Composite structure of human FASN with NADPH in State 1
Summary for 8VLE
| Entry DOI | 10.2210/pdb8vle/pdb |
| EMDB information | 43337 |
| Descriptor | Fatty acid synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (2 entities in total) |
| Functional Keywords | megasynthase, lipogenesis, biosynthetic protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 560426.12 |
| Authors | Schultz, K.,Marmorstein, R. (deposition date: 2024-01-11, release date: 2025-02-26, Last modification date: 2025-05-14) |
| Primary citation | 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 Cited by 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: 39979457DOI: 10.1038/s41586-025-08587-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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