PDBsum entry 6fns

Transferase

PDB id: 6fns

Contents

Protein chains

322 a.a.

Ligands

DY8 ×2

GOL ×2

Waters ×479

PDB id:

6fns

Name:

Transferase

Title:

Ergothioneine-biosynthetic methyltransferase egtd in complex with morpholinohistidine

Structure:

Histidine n-alpha-methyltransferase. Chain: a, b. Fragment: egtd. Synonym: histidine trimethyltransferase. Engineered: yes

Source:

Mycobacterium smegmatis. Organism_taxid: 1772. Gene: egtd, ers451418_06055. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.85Å R-factor: 0.164 R-free: 0.184

Authors:

A.Vit,W.Blankenfeldt,F.P.Seebeck

Key ref:

L.Misson et al. (2018). Inhibition and Regulation of the Ergothioneine Biosynthetic Methyltransferase EgtD. ACS Chem Biol, 13, 1333-1342. PubMed id: 29658702 DOI: 10.1021/acschembio.8b00127

Date:

05-Feb-18 Release date: 13-Jun-18

Protein chains

A0R5M8  (EGTD_MYCS2) -  Histidine N-alpha-methyltransferase from Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155)

Seq: 321 a.a.

Struc: 322 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.1.1.44 - L-histidine N(alpha)-methyltransferase.
• Reaction: L-histidine + 3 S-adenosyl-L-methionine = hercynine + 3 S-adenosyl-L- homocysteine + 3 H⁺

L-histidine + 3 × S-adenosyl-L-methionine = hercynine + 3 × S-adenosyl-L- homocysteine (Bound ligand (Het Group name = DY8) matches with 76.47% similarity) + 3 × H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acschembio.8b00127

ACS Chem Biol 13:1333-1342 (2018)

PubMed id: 29658702

Inhibition and Regulation of the Ergothioneine Biosynthetic Methyltransferase EgtD.

L.Misson, R.Burn, A.Vit, J.Hildesheim, M.A.Beliaeva, W.Blankenfeldt, F.P.Seebeck.

ABSTRACT

Ergothioneine is an emerging factor in cellular redox homeostasis in bacteria, fungi, plants, and animals. Reports that ergothioneine biosynthesis may be important for the pathogenicity of bacteria and fungi raise the question as to how this pathway is regulated and whether the corresponding enzymes may be therapeutic targets. The first step in ergothioneine biosynthesis is catalyzed by the methyltransferase EgtD that converts histidine into N-α-trimethylhistidine. This report examines the kinetic, thermodynamic and structural basis for substrate, product, and inhibitor binding by EgtD from Mycobacterium smegmatis. This study reveals an unprecedented substrate binding mechanism and a fine-tuned affinity landscape as determinants for product specificity and product inhibition. Both properties are evolved features that optimize the function of EgtD in the context of cellular ergothioneine production. On the basis of these findings, we developed a series of simple histidine derivatives that inhibit methyltransferase activity at low micromolar concentrations. Crystal structures of inhibited complexes validate this structure- and mechanism-based design strategy.