We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plas...

P-glycoprotein (P-gp, ABCB1) is an ATP-binding cassette drug pump that protects us from toxic compounds and confers multidrug resistance. Each homologous half contains a transmembrane domain with six transmembrane segments followed by a nucleotide-binding domain (NBD). The drug- and ATP-binding sites reside at the interface between the transmembrane domain and NBDs, respectively. Drug binding a...

Neuronal loss and axonal degeneration are important pathological features of many neurodegenerative diseases. The molecular mechanisms underlying the majority of axonal degeneration conditions remain unknown. To better understand axonal degeneration, we studied a mouse mutant wabbler-lethal (wl). Wabbler-lethal (wl) mutant mice develop progressive ataxia with pronounced neurodegeneration in the...

Vaccinia virus early transcription factor (VETF) activates the transcription of early gene templates by the viral RNA polymerase. VETF is a heterodimeric protein that binds to transcription promoters and has an associated DNA-dependent ATPase activity. The small subunit of VETF has sequences resembling two motifs commonly found in ATPases: an A-type ATP binding motif and a DEAH box. To investig...

In the presence of ascorbate/H(2)O(2), Fe(2+) ions or the ATP-Fe(2+) complex catalyze selective cleavage of the alpha subunit of gastric H(+),K(+)-ATPase. The electrophoretic mobilities of the fragments and dependence of the cleavage patterns on E(1) and E(2) conformational states are essentially identical to those described previously for renal Na(+),K(+)-ATPase. The cleavage pattern of H(+),K...

In the presence of ascorbate/H2O2, Fe 2 ions or the ATP-Fe complex catalyze selective cleavage of the subunit of gastric H ,K -ATPase. The electrophoretic mobilities of the fragments and dependence of the cleavage patterns on E1 and E2 conformational states are essentially identical to those described previously for renal Na ,K -ATPase. The cleavage pattern of H ,K ATPase by Fe ions is consiste...

P-type ATPases catalyze the active transport of cations and phospholipids across biological membranes. Members of this large family are involved in a range of fundamental cellular processes. To date, a substantial number of P-type ATPase inhibitors have been characterized, some of which are used as drugs. In this work a library of natural compounds was screened and we first identified curcumino...

ATP-driven acidification of internal compartments of Trypanosoma cruzi epimastigotes was assayed spectrophotometrically with Acridine Orange and cells permeabilized with filipin. H+-ATPase activity was not inhibited fully by either 500 nM concanamycin A or 500 microM orthovanadate, but a combination of 5 nM concanamycin A and 25 microM vanadate completely inhibited activity, suggesting the oper...

The subcellular locations of Ca(2+)-ATPases in the membranes of cauliflower (Brassica oleracea L.) inflorescences were investigated. After continuous sucrose gradient centrifugation a 111-kD calmodulin (CaM)-stimulated and caM-binding Ca(2+)-ATPase (BCA1; P. Askerlund [1996] Plant Physiol 110: 913-922; S. Malmström, P. Askerlund, M.G. Plamgren [1997] FEBS Lett 400: 324-328) comigrated with vacu...