6WTF

Structure of radical S-adenosylmethionine methyltransferase, TsrM, from Kitasatospora setae with tryptophan substrate and SAM analog (aza-SAM) bound

Summary for 6WTF

• Entry DOI: 10.2210/pdb6wtf/pdb
• Related: 6WTE
• Descriptor: Tryptophan-C2-methyltransferase containing B12-binding domain, IRON/SULFUR CLUSTER, COBALAMIN, ... (6 entities in total)
• Functional Keywords: radical sam, cobalamin, fes cluster, methyltransferase, transferase
• Biological source: Kitasatospora setae
• Total number of polymer chains: 2
• Total formula weight: 132808.52

Authors

Knox, H.L.,Chen, P.Y.-T.,Drennan, C.L.,Booker, S.J. (deposition date: 2020-05-02, release date: 2020-12-23, Last modification date: 2023-10-18)

Primary citation

Knox, H.L.,Chen, P.Y.,Blaszczyk, A.J.,Mukherjee, A.,Grove, T.L.,Schwalm, E.L.,Wang, B.,Drennan, C.L.,Booker, S.J.
Structural basis for non-radical catalysis by TsrM, a radical SAM methylase.
Nat.Chem.Biol., 17:485-491, 2021

PubMed Abstract: Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of L-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5'-deoxyadenosyl 5'-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe-4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion.

PubMed: 33462497
DOI: 10.1038/s41589-020-00717-y

Experimental method

X-RAY DIFFRACTION (2.19 Å)