4f9v | pdb_00004f9v

Structure of C113A/C136A mutant variant of glycosylated glutaminyl cyclase from Drosophila melanogaster

spinqualitylabelsall models 4f9v, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4f9v is a 2 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: BMA, MAN, NAG, PBD, PEG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function QPCT1_DROME Acts as a glutaminyl-peptide cyclotransferase (PubMed:17722885, PubMed:22897232). Responsible for the biosynthesis of pyroglutamyl peptides (By similarity). Might be more efficient in the conversion of tri and tetrapeptides in vitro (PubMed:17722885). Might have a relative preference for substrates containing hydrophobic amino acids in vitro (PubMed:17722885).[UniProtKB:Q16769] Publication Abstract from PubMed Glutaminyl cyclases (QCs), which catalyze the formation of pyroglutamic acid (pGlu) at the N-terminus of a variety of peptides and proteins, have attracted particular attention for their potential role in Alzheimer's disease. In a transgenic Drosophila melanogaster (Dm) fruit fly model, oral application of the potent competitive QC inhibitor PBD150 was shown to reduce the burden of pGlu-modified Abeta. In contrast to mammals such as humans and rodents, there are at least three DmQC species, one of which (isoDromeQC) is localized to mitochondria, whereas DromeQC and an isoDromeQC splice variant possess signal peptides for secretion. Here we present the recombinant expression, characterization and crystal structure determination of mature DromeQC and isoDromeQC, revealing a similar overall fold to mammalian QCs. In the case of isoDromeQC, the putative extended substrate binding site might be affected by proximity of the N-terminal residues. PBD150 inhibition of DromeQC is roughly one order of magnitude lower than that of the human and murine QCs. The inhibitor binds to isoDromeQC in a similar fashion to that observed for human QCs, whereas it adopts alternative binding modes in a DromeQC variant lacking the conserved cysteines near to the active center and shows a disordered dimethoxyphenyl moiety in wild type DromeQC, providing an explanation for the lower affinity. Our biophysical and structural data suggest that isoDromeQC and human QC are similar with regard to functional aspects. The two Dm enzymes represent a suitable model for further in depth analysis of the catalytic mechanism of animal QCs, and isoDromeQC might serve as a model system for structure based design of potential AD therapeutics. Crystal Structures of Glutaminyl Cyclases from Drosophila melanogaster Reveal Active Site Conservation between Insect and Mammalian QCs.,Koch B, Kolenko P, Buchholz M, Ruiz Carrillo D, Parthier C, Wermann M, Rahfeld JU, Reuter G, Schilling S, Stubbs MT, Demuth HU Biochemistry. 2012 Aug 16. PMID:22897232 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutaminyl cyclase

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