8EYK

Atomic model of the core modifying region of human fatty acid synthase in complex with TVB-2640

Summary for 8EYK

• Entry DOI: 10.2210/pdb8eyk/pdb
• EMDB information: 28691
• Descriptor: Fatty acid synthase, denifanstat, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• Functional Keywords: fatty acid synthase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 369358.82

Authors

Hasan, S.M.N.,Keszei, A.,Mazhab-Jafari, M.T. (deposition date: 2022-10-27, release date: 2023-05-24, Last modification date: 2024-06-19)

Primary citation

Hasan, S.M.N.,Lou, J.W.,Keszei, A.F.A.,Dai, D.L.,Mazhab-Jafari, M.T.
Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat.
Nat Commun, 14:3460-3460, 2023

PubMed Abstract: Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a 16-carbon chain fatty acid that is the primary precursor of lipid metabolism and an important intracellular signaling molecule. FASN is an attractive drug target in diabetes, cancer, fatty liver diseases, and viral infections. Here, we develop an engineered full-length human FASN (hFASN) that enables isolation of the condensing and modifying regions of the protein post-translation. The engineered protein enables electron cryo-microscopy (cryoEM) structure determination of the core modifying region of hFASN to 2.7 Å resolution. Examination of the dehydratase dimer within this region reveals that unlike its close homolog, porcine FASN, the catalytic cavity is close-ended and is accessible only through one opening in the vicinity of the active site. The core modifying region exhibits two major global conformational variabilities that describe long-range bending and twisting motions of the complex in solution. Finally, we solved the structure of this region bound to an anti-cancer drug, Denifanstat (i.e., TVB-2640), demonstrating the utility of our approach as a platform for structure guided design of future hFASN small molecule inhibitors.

PubMed: 37308485
DOI: 10.1038/s41467-023-39266-y

Experimental method

ELECTRON MICROSCOPY (2.7 Å)