4JNA

Crystal structure of the DepH complex with dimethyl-FK228

Summary for 4JNA

• Entry DOI: 10.2210/pdb4jna/pdb
• Related: 4JN9
• Related PRD ID: PRD_001184
• Descriptor: DepH, Dimethyl FK228, FLAVIN-ADENINE DINUCLEOTIDE, ... (8 entities in total)
• Functional Keywords: disulfide bond formation, fk228, depsipeptide, fad-dependent oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Chromobacterium violaceum
• Total number of polymer chains: 4
• Total formula weight: 76757.86

Authors

Li, J.,Wang, C.,Zhang, Z.M.,Zhou, J.H.,Cheng, E. (deposition date: 2013-03-14, release date: 2014-03-05, Last modification date: 2023-11-15)

Primary citation

Li, J.,Wang, C.,Zhang, Z.M.,Cheng, Y.Q.,Zhou, J.
The structural basis of an NADP+-independent dithiol oxidase in FK228 biosynthesis.
Sci Rep, 4:4145-4145, 2014

PubMed Abstract: The disulfide bond is unusual in natural products and critical for thermal stability, cell permeability and bioactivity. DepH from Chromobacterium violaceum No. 968 is an FAD-dependent enzyme responsible for catalyzing the disulfide bond formation of FK228, an anticancer prodrug approved for the treatment of cutaneous T-cell lymphoma. Here we report the crystal structures of DepH and DepH complexed with a substrate analogue S,S'-dimethyl FK228 at 1.82 Å and 2.00 Å, respectively. Structural and biochemical analyses revealed that DepH, in contrast to the well characterized low molecular weight thioredoxin reductases (LMW TrxRs), is an NADP(+)-independent dithiol oxidase. DepH not only lacks a conserved GGGDXAXE motif necessary for NADP(+) binding in the canonical LMW TrxRs, but also contains a 11-residue sequence which physically impedes the binding of NADP(+). These observations explain the difference between NADP(+)-independent small molecule dithiol oxidases and NADP(+)-dependent thioredoxin reductases and provide insights for understanding the catalytic mechanism of dithiol oxidases involved in natural product biosynthesis.

PubMed: 24553401
DOI: 10.1038/srep04145

Experimental method

X-RAY DIFFRACTION (2 Å)