Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers

F. Fernandes, L. Loura, R.B.M. Koehorst, N. Dixon, T.P. Kee, M.A. Hemminga, M. Prieto

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyi)-2-methoxy-N-(1,2,2,6,6-pentamethylpip eridin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.
Original languageEnglish
Pages (from-to)5271-5279
JournalBiochemistry
Volume45
Issue number16
DOIs
Publication statusPublished - 2006

Fingerprint

Vacuolar Proton-Translocating ATPases
Lipid bilayers
Lipid Bilayers
Adenosine Triphosphatases
Membranes
Molecular recognition
Molecules
Fluorescence
Lipids
Enzymes
indole
SB 242784

Keywords

  • membrane penetration depth
  • v-atpase
  • bone-resorption
  • fluorescence polarization
  • selective inhibitor
  • linear dichroism
  • energy-transfer
  • bafilomycin
  • orientation
  • tryptophan

Cite this

Fernandes, F., Loura, L., Koehorst, R. B. M., Dixon, N., Kee, T. P., Hemminga, M. A., & Prieto, M. (2006). Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers. Biochemistry, 45(16), 5271-5279. https://doi.org/10.1021/bi0522753
Fernandes, F. ; Loura, L. ; Koehorst, R.B.M. ; Dixon, N. ; Kee, T.P. ; Hemminga, M.A. ; Prieto, M. / Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers. In: Biochemistry. 2006 ; Vol. 45, No. 16. pp. 5271-5279.
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Fernandes, F, Loura, L, Koehorst, RBM, Dixon, N, Kee, TP, Hemminga, MA & Prieto, M 2006, 'Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers', Biochemistry, vol. 45, no. 16, pp. 5271-5279. https://doi.org/10.1021/bi0522753

Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers. / Fernandes, F.; Loura, L.; Koehorst, R.B.M.; Dixon, N.; Kee, T.P.; Hemminga, M.A.; Prieto, M.

In: Biochemistry, Vol. 45, No. 16, 2006, p. 5271-5279.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers

AU - Fernandes, F.

AU - Loura, L.

AU - Koehorst, R.B.M.

AU - Dixon, N.

AU - Kee, T.P.

AU - Hemminga, M.A.

AU - Prieto, M.

N1 - ISI Document Delivery No.: 036CV Times Cited: 1 Cited Reference Count: 40

PY - 2006

Y1 - 2006

N2 - The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyi)-2-methoxy-N-(1,2,2,6,6-pentamethylpip eridin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.

AB - The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyi)-2-methoxy-N-(1,2,2,6,6-pentamethylpip eridin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.

KW - membrane penetration depth

KW - v-atpase

KW - bone-resorption

KW - fluorescence polarization

KW - selective inhibitor

KW - linear dichroism

KW - energy-transfer

KW - bafilomycin

KW - orientation

KW - tryptophan

U2 - 10.1021/bi0522753

DO - 10.1021/bi0522753

M3 - Article

VL - 45

SP - 5271

EP - 5279

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 16

ER -