5WHY

Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides

Summary for 5WHY

• Entry DOI: 10.2210/pdb5why/pdb
• Related: 5WGG
• Descriptor: Radical SAM domain protein, IRON/SULFUR CLUSTER, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: radical sam binding, metalloprotein, sciff maturase, spasm domain-containing, peptide binding protein
• Biological source: Clostridium thermocellum (strain ATCC 27405 / DSM 1237 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372)
• Total number of polymer chains: 2
• Total formula weight: 107677.27

Authors

Grove, T.L.,Himes, P.,Bowers, A.,Bonanno, J.B.,Almo, S.C. (deposition date: 2017-07-18, release date: 2017-07-26, Last modification date: 2023-10-04)

Primary citation

Grove, T.L.,Himes, P.M.,Hwang, S.,Yumerefendi, H.,Bonanno, J.B.,Kuhlman, B.,Almo, S.C.,Bowers, A.A.
Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides.
J. Am. Chem. Soc., 139:11734-11744, 2017

PubMed Abstract: Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2.04 Å resolution. CteB has the (β/α)-TIM barrel fold that is characteristic of radical SAM enzymes, as well as a C-terminal SPASM domain that contains two auxiliary [4Fe-4S] clusters. Importantly, one [4Fe-4S] cluster in the SPASM domain exhibits an open coordination site in absence of peptide substrate, which is coordinated by a peptidyl-cysteine residue in the bound state. The crystal structure of CteB also reveals an accessory N-terminal domain that has high structural similarity to a recently discovered motif present in several enzymes that act on ribosomally synthesized and post-translationally modified peptides (RiPPs), known as a RiPP precursor peptide recognition element (RRE). This crystal structure is the first of a sactionine bond forming enzyme and sheds light on structures and mechanisms of other members of this class such as AlbA or ThnB.

PubMed: 28704043
DOI: 10.1021/jacs.7b01283

Experimental method

X-RAY DIFFRACTION (2.692 Å)