Journal
FEBS LETTERS
Volume 591, Issue 15, Pages 2348-2361Publisher
WILEY
DOI: 10.1002/1873-3468.12753
Keywords
Gcn5-related N-acetyltransferase; product-based transitionstate modeling; radical-mediated bisubstrate
Funding
- San Francisco State University
- National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
- U.S. Department of Health and Human Services [HHSN 272200700058C, HHSN272201200026C]
- NIH [U54 GM094585]
- U.S. DOE Office of Biological and Environmental Research [DE-AC02-06CH11357]
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Gcn5-related N-acetyltransferases (GNATs) are found in all kingdoms of life and catalyze important acyl transfer reactions in diverse cellular processes. While many 3D structures of GNATs have been determined, most do not contain acceptor substrates in their active sites. To expand upon existing crystallographic strategies for improving acceptor-bound GNAT structures, we synthesized peptide substrate analogs and reacted them with CoA in PA4794 protein crystals. We found two separate mechanisms for bisubstrate formation: (a) a novel X-ray induced radical-mediated alkylation of CoA with an alkene peptide and (b) direct alkylation of CoA with a halogenated peptide. Our approach is widely applicable across the GNAT superfamily and can be used to improve the success rate of obtaining liganded structures of other acyltransferases.
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