Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis
- Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States); San Francisco State Univ., San Francisco, CA (United States)
- Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States)
- San Francisco State Univ., San Francisco, CA (United States)
- Northwestern Univ., Argonne, IL (United States)
- Univ. of Minnesota, Minneapolis, MN (United States)
- Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States); Univ. of Minnesota, Minneapolis, MN (United States)
Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. As a result, the structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Allergy and Infectious Diseases; National Inst. of Health; Dept. of Health and Human Services; Bill and Melinda Gates Foundation
- Grant/Contract Number:
- AC02-06CH11357; HHSN272200700058C; HHSN272201200026C; 1-U54-AI-057153; AI070291
- OSTI ID:
- 1352272
- Journal Information:
- ACS Infectious Diseases, Vol. 2, Issue 8; ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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