8AD8

Flavin-dependent tryptophan 6-halogenase Thal in complex with a D-Trp-Ser dipeptide

Summary for 8AD8

• Entry DOI: 10.2210/pdb8ad8/pdb
• Related: 6H43 6H44 6IB5 6SLS 6SLT 7AQU 7AQV 7CU0 7CU1 7CU2 8AD7
• Descriptor: Tryptophan 6-halogenase, GLYCEROL, D-tryptophyl-L-serine, ... (5 entities in total)
• Functional Keywords: halogenase, thdh, dipeptide, unnatural substrate, tryptophan halogenase, flavoprotein
• Biological source: Streptomyces albogriseolus
• Total number of polymer chains: 2
• Total formula weight: 121124.43

Authors

Gafe, S.,Moritzer, A.C.,Montua, N.,Sewald, N.,Niemann, H.H. (deposition date: 2022-07-08, release date: 2022-10-12, Last modification date: 2024-02-07)

Primary citation

Schnepel, C.,Moritzer, A.C.,Gafe, S.,Montua, N.,Minges, H.,Niess, A.,Niemann, H.H.,Sewald, N.
Enzymatic Late-Stage Halogenation of Peptides.
Chembiochem, 24:e202200569-e202200569, 2023

PubMed Abstract: The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or conjugation of bioactive compounds. The development of orthogonal methods for C-H functionalisation is crucial for such peptide derivatisation. Among them, biocatalytic methods are increasingly attracting attention. Tryptophan halogenases emerged as valuable catalysts to functionalise tryptophan (Trp), while direct enzyme-catalysed halogenation of synthetic peptides is yet unprecedented. Here, it is reported that the Trp 6-halogenase Thal accepts a wide range of amides and peptides containing a Trp moiety. Increasing the sequence length and reaction optimisation made bromination of pentapeptides feasible with good turnovers and a broad sequence scope, while regioselectivity turned out to be sequence dependent. Comparison of X-ray single crystal structures of Thal in complex with d-Trp and a dipeptide revealed a significantly altered binding mode for the peptide. The viability of this bioorthogonal approach was exemplified by halogenation of a cyclic RGD peptide.

PubMed: 36259362
DOI: 10.1002/cbic.202200569

Experimental method

X-RAY DIFFRACTION (2.95 Å)