The Crystal and Molecular Structure of the Sesquiterpenoid Silerin (Trilobolide)

Kutschabsky, L.; Kretschmer, R.‐G.; Ripperger, Helmut

doi:10.1002/crat.2170210513

Cited by 4 publications

(2 citation statements)

References 4 publications

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“…The hydroxyl groups on BHQ are also essential for activity, with neither 2,5-di-ierf-butyl-1,4-quinone nor 2,5di-ferf-butyl-1,4-dihydroxybenzene diacetate inhibiting the ATPase (Wictome et al, 1994). However, the separation between the two essential -OH groups in crystals of trilobolide (3.64 Á; Kutschabsky et al, 1986) is very different to that predicted by modeling for BHQ (5.52 Á). Thus it is unlikely that the same residues on the ATPase could be involved in interaction with the -OH residues of the sesquiterpene lactones and the 1,4-dihydroxybenzenes.…”

Section: Resultsmentioning

confidence: 81%

Interactions of Dihydroxybenzenes with the Ca2+-ATPase: Separate Binding Sites for Dihydroxybenzenes and Sesquiterpene Lactones

Ym¹,

Wictome²,

Jm³

et al. 1995

Biochemistry

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The Ca(2+)-ATPase of skeletal muscle sarcoplasmic reticulum is inhibited by 2,5-di-tert-butyl-1,4-dihydroxybenzene (BHQ) and other hydrophobic 1,4-dihydroxybenzenes. Inhibitory potency increases on increasing substituent chain length from 2,5-dipropyl-1,4-dihydroxybenzene to 2,5-di-tert-amyl-1,4-dihydroxybenzene, the most potent inhibitor, but then decreases for 2,5-bis(7-methylheptyl)-1,4-dihydroxybenzene. Kinetic measurements are consistent with isomerization following the initial binding of BHQ to the ATPase to give a modified E2 conformation, E2AI, as for the binding of sesquiterpene lactones, such as thapsigargin. Binding of BHQ to the ATPase shifts the E1-E2 equilibrium toward E2 because of the formation of E2AI. Measurements of Ca2+ binding as a function of BHQ concentration suggest that BHQ can bind to the E1 conformation of the ATPase (but without the subsequent conformational change observed on binding to E2) and that the binding constants of E1 for Ca2+ are unaffected by binding of BHQ. Binding of BHQ to the ATPase in the presence of substoichiometric amounts of thapsivillosin A and effects of mixtures of BHQ and thapsivillosin A show that these two inhibitors have separate binding sites on the ATPase.

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Section: Resultsmentioning

confidence: 81%

Interactions of Dihydroxybenzenes with the Ca2+-ATPase: Separate Binding Sites for Dihydroxybenzenes and Sesquiterpene Lactones

Ym¹,

Wictome²,

Jm³

et al. 1995

Biochemistry

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“…Sesquiterpene lactones related to thapsigargin are specific inhibitors of the Ca2+-ATPase of sarcoplasmic reticulum (SR) and of endoplasmic reticulum, with no effects on the Ca21-ATPase of the plasma membrane or on other P-type ATPases [1][2][3][4][5]. Members of this class of inhibitor include thapsigargin itself and thapsigargicin, both isolated from Thapsia garganica [6], thapsivillosin A (TvA) isolated from Thapsia villosa [7][8][9] and trilobolide, extracted from Laser trilobum [9,10] (for structures, see insert to Figure 1). The inhibitors are of high affinity, e.g.…”

Section: Introductionmentioning

confidence: 99%

Binding of sesquiterpene lactone inhibitors to the Ca2+-ATPase

Wictome

Khan

East

et al. 1995

Biochemical Journal

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The mechanism of inhibition of the Ca(2+)-ATPase from sarcoplasmic reticulum by the sesquiterpene lactones thapsigargin, trilobolide and thapsivillosin A (TvA) has been determined. A decrease in the affinity of the ATPase for Ca2+ is observed in the presence of the inhibitors (I), consistent with a shift in the E1/E2 equilibrium for the ATPase towards E2 forms. Amounts of inhibitor beyond a 1:1 molar ratio with ATPase produce no further decrease in affinity for Ca2+, inconsistent with the formation of a dead-end complex. Measurements of the rate of quenching of the tryptophan fluorescence of the ATPase by TvA are consistent with an association step to give E2I followed by an isomerization to a modified state E2AI. The kinetics of the reversal of the effects of TvA by Ca2+ at sub-stoichiometric amounts of TvA are bi-exponential, with a fast component whose rate is independent of TvA concentration and equal to the rate observed in the absence of TvA, and a slow component whose rate decreases with increasing TvA concentration. These observations are also consistent with the formation of a modified state E2AI following the initial binding of I to E2. The equilibrium constant E2AI/E2I increases in the order TvA < trilobolide < thapsigargin. The results suggest that the effects of the inhibitors on the overall ratio of E2 to E1 forms of the ATPase follow largely from the formation of E2AI from E2I, and that binding constants are very similar for E1Ca2, E1 and E2.

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Structural changes in the calcium pump accompanying the dissociation of calcium

Toyoshima

Nomura

2002

Nature

857

986

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In skeletal muscle, calcium ions are transported (pumped) against a concentration gradient from the cytoplasm into the sarcoplasmic reticulum, an intracellular organelle. This causes muscle cells to relax after cytosolic calcium increases during excitation. The Ca(2+) ATPase that carries out this pumping is a representative P-type ion-transporting ATPase. Here we describe the structure of this ion pump at 3.1 A resolution in a Ca(2+)-free (E2) state, and compare it with that determined previously for the Ca(2+)-bound (E1Ca(2+)) state. The structure of the enzyme stabilized by thapsigargin, a potent inhibitor, shows large conformation differences from that in E1Ca(2+). Three cytoplasmic domains gather to form a single headpiece, and six of the ten transmembrane helices exhibit large-scale rearrangements. These rearrangements ensure the release of calcium ions into the lumen of sarcoplasmic reticulum and, on the cytoplasmic side, create a pathway for entry of new calcium ions.

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The Crystal and Molecular Structure of the Sesquiterpenoid Silerin (Trilobolide)

Abstract: For the title compound a guaianolide structure is shown by X‐ray analysis. Only the relative configuration of the molecule could be established.

Cited by 4 publications

References 4 publications

Interactions of Dihydroxybenzenes with the Ca2+-ATPase: Separate Binding Sites for Dihydroxybenzenes and Sesquiterpene Lactones

Interactions of Dihydroxybenzenes with the Ca2+-ATPase: Separate Binding Sites for Dihydroxybenzenes and Sesquiterpene Lactones

Binding of sesquiterpene lactone inhibitors to the Ca2+-ATPase

Structural changes in the calcium pump accompanying the dissociation of calcium

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