6O5J

Crystal Structure of DAD2 bound to quinazolinone derivative

6O5J の概要

• エントリーDOI: 10.2210/pdb6o5j/pdb
• 関連するPDBエントリー: 4DNP 6AP6 6AP7
• 分子名称: Probable strigolactone esterase DAD2, 1-(4-hydroxy-3-nitrophenyl)quinazoline-2,4(1H,3H)-dione, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: alpha/beta hydrolase, hormone
• 由来する生物種: Petunia hybrida (Petunia)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59801.07

構造登録者

Hamiaux, C. (登録日: 2019-03-03, 公開日: 2019-06-26, 最終更新日: 2023-10-11)

主引用文献

Hamiaux, C.,Larsen, L.,Lee, H.W.,Luo, Z.,Sharma, P.,Hawkins, B.C.,Perry, N.B.,Snowden, K.C.
Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode.
Biochem.J., 476:1843-1856, 2019

PubMed Abstract: Strigolactones (SLs) are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, SLs are recognized by α/β hydrolase-fold proteins from the D14/DAD2 (Dwarf14/Decreased Apical Dominance 2) family in the initial step of the signaling pathway. We have previously discovered that -phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of SL receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial docking studies suggested that these compounds would bind to DAD2, the petunia SL receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in assays acted as a competitive antagonist of SL receptors, with reduced affinity and potency compared with its -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 , highlighting a novel inhibition mechanism for SL receptors. Despite a ∼10-fold difference in potency , the QADD and tolfenamic acid had comparable activity , 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 SL receptors.

PubMed: 31186286
DOI: 10.1042/BCJ20190288

実験手法

X-RAY DIFFRACTION (1.63 Å)