4hka

Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase in complex with HEME

spinqualitylabelsall models 4hka, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hka is a 1 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM Gene: v, CG5163 (Drosophila melanogaster) Activity: Tryptophan 2,3-dioxygenase, with EC number 1.13.11.11 Resources: FirstGlance, OCA, RCSB, PDBsum Function [T23O_DROME] Catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring (By similarity). Required during larval growth to control the level of potentially harmful free tryptophan in the hemolymph. In the adult the same reaction is the first step in the ommochrome biosynthetic pathway. Publication Abstract from PubMed Tryptophan 2,3-dioxygenase (TDO) catalyzes the oxidative cleavage of the indole ring of l-tryptophan to N-formylkynurenine in the kynurenine pathway, and is considered as a drug target for cancer immunotherapy. Here, we report the first crystal structure of a eukaryotic TDO from Drosophila melanogaster (DmTDO) in complex with heme at 2.7A resolution. DmTDO consists of an N-terminal segment, a large domain and a small domain, and assumes a tetrameric architecture. Compared with prokaryotic TDOs, DmTDO contains two major insertion sequences: one forms part of the heme-binding site and the other forms a large portion of the small domain. The small domain which is unique to eukaryotic TDOs, interacts with the active site of an adjacent monomer and plays a role in the catalysis. Molecular modeling and dynamics simulation of DmTDO-heme-Trp suggest that like prokaryotic TDOs, DmTDO adopts an induced-fit mechanism to bind l-Trp; in particular, two conserved but flexible loops undergo conformational changes, converting the active site from an open conformation to a closed conformation. The functional roles of the key residues involved in recognition and binding of the heme and the substrate are verified by mutagenesis and kinetic studies. In addition, a modeling study of DmTDO in complex with the competitive inhibitor LM10 provides useful information for further inhibitor design. These findings reveal insights into the substrate recognition and the catalysis of DmTDO and possibly other eukaryotic TDOs and shed lights on the development of effective anti-TDO inhibitors. Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism.,Huang W, Gong Z, Li J, Ding J J Struct Biol. 2013 Mar;181(3):291-9. doi: 10.1016/j.jsb.2013.01.002. Epub 2013, Jan 17. PMID:23333332 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dioxygenase

Proteopedia Page Contributors and Editors (what is this?)

OCA