3ACW

Crystal structure of the C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus complexed with BPH-651

3ACW の概要

• エントリーDOI: 10.2210/pdb3acw/pdb
• 関連するPDBエントリー: 2ZCO 2ZCP 2ZCQ 2ZCR 2ZCS 2ZY1 3ACX 3ACY
• 分子名称: Dehydrosqualene synthase, (3R)-3-biphenyl-4-yl-1-azabicyclo[2.2.2]octan-3-ol (3 entities in total)
• 機能のキーワード: crtm, carotenoid biosynthesis, staphyloxanthin biosynthesis, transferase, head-to-head condensation, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35066.87

構造登録者

Liu, C.I.,Jeng, W.Y.,Wang, A.H.J.,Oldfield, E. (登録日: 2010-01-13, 公開日: 2010-11-24, 最終更新日: 2023-11-01)

主引用文献

Lin, F.Y.,Liu, C.I.,Liu, Y.L.,Zhang, Y.,Wang, K.,Jeng, W.Y.,Ko, T.P.,Cao, R.,Wang, A.H.J.,Oldfield, E.
Mechanism of action and inhibition of dehydrosqualene synthase
Proc.Natl.Acad.Sci.USA, 107:21337-21342, 2010

PubMed Abstract: "Head-to-head" terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene synthase (CrtM) complexed with its reaction intermediate, presqualene diphosphate (PSPP), the dehydrosqualene (DHS) product, as well as a series of inhibitors. The results indicate that, on initial diphosphate loss, the primary carbocation so formed bends down into the interior of the protein to react with C2,3 double bond in the prenyl acceptor to form PSPP, with the lower two-thirds of both PSPP chains occupying essentially the same positions as found in the two farnesyl chains in the substrates. The second-half reaction is then initiated by the PSPP diphosphate returning back to the Mg(2+) cluster for ionization, with the resultant DHS so formed being trapped in a surface pocket. This mechanism is supported by the observation that cationic inhibitors (of interest as antiinfectives) bind with their positive charge located in the same region as the cyclopropyl carbinyl group; that S-thiolo-diphosphates only inhibit when in the allylic site; activity results on 11 mutants show that both DXXXD conserved domains are essential for PSPP ionization; and the observation that head-to-tail isoprenoid synthases as well as terpene cyclases have ionization and alkene-donor sites which spatially overlap those found in CrtM.

PubMed: 21098670
DOI: 10.1073/pnas.1010907107

実験手法

X-RAY DIFFRACTION (1.63 Å)