6o5j

Crystal Structure of DAD2 bound to quinazolinone derivative

spinqualitylabelsall models 6o5j, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6o5j is a 2 chain structure with sequence from Petunia x hybrida. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.63Å Ligands: ACT, GOL, LM7, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DAD2_PETHY Publication Abstract from PubMed Strigolactones are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, strigolactones are recognized by alpha/beta hydrolase fold proteins from the D14/DAD2 family in the initial step of the signalling pathway. We have previously discovered that N -phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of strigolactone receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial in silico docking studies suggested that these compounds would bind to DAD2, the petunia strigolactone receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in in vitro assays acted as a competitive antagonist of strigolactone receptors, with reduced affinity and potency compared with its N -phenylanthranilic acid "parent". X-ray crystal structure analysis revealed that the binding mode of the active QADD inside DAD2's cavity was not that predicted in silico , highlighting a novel inhibition mechanism for strigolactone receptors. Despite a ~10-fold difference in potency in vitro , the QADD and tolfenamic acid had comparable activity in planta , suggesting that the QADD compensates for lower potency with increased bioavailability. Altogether, our results establish this QADD as a novel lead compound towards the development of potent and bioavailable antagonists of strigolactone receptors. Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode.,Hamiaux C, Larsen L, Lee HW, Luo Z, Sharma P, Hawkins BC, Perry NB, Snowden KC Biochem J. 2019 Jun 11. pii: BCJ20190288. doi: 10.1042/BCJ20190288. PMID:31186286 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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