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TitleAtomic model for core modifying region of human fatty acid synthase in complex with Denifanstat.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3460, Year 2023
Publish dateJun 12, 2023
AuthorsS M Naimul Hasan / Jennifer W Lou / Alexander F A Keszei / David L Dai / Mohammad T Mazhab-Jafari /
PubMed AbstractFatty 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 ...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.
External linksNat Commun / PubMed:37308485 / PubMed Central
MethodsEM (single particle)
Resolution2.45 - 2.7 Å
Structure data

28690

8eyi

EMDB-28690, PDB-8eyi:
Atomic model of the core modifying region of human fatty acid synthase
Method: EM (single particle) / Resolution: 2.7 Å

28691

8eyk

EMDB-28691, PDB-8eyk:
Atomic model of the core modifying region of human fatty acid synthase in complex with TVB-2640
Method: EM (single particle) / Resolution: 2.7 Å

40182

8gkc

EMDB-40182, PDB-8gkc:
Atomic model of the core modifying region of human fatty acid synthase in complex with TVB-2640 - C2 refinement
Method: EM (single particle) / Resolution: 2.45 Å

Chemicals

ChemComp-NDP:
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate

ChemComp-X5O:
denifanstat

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Fatty acid synthase / TRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR complex

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