EPR Studies of V-ATPase with Spin-Labeled Inhibitors DCC and Archazolid: Interaction Dynamics with Proton Translocating Subunit c

DC ElementWertSprache
dc.contributor.authorGoelz, Jan Philipp
dc.contributor.authorBockelmann, Svenja
dc.contributor.authorMayer, Kerstin
dc.contributor.authorSteinhoff, Heinz-Juergen
dc.contributor.authorWieczorek, Helmut
dc.contributor.authorHuss, Markus
dc.contributor.authorKlare, Johann P.
dc.contributor.authorMenche, Dirk
dc.date.accessioned2021-12-23T16:16:53Z-
dc.date.available2021-12-23T16:16:53Z-
dc.date.issued2016
dc.identifier.issn18607179
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/12089-
dc.description.abstractVacuolar-type H+-ATPases (V-ATPases) have gained recent attention as highly promising anticancer drug targets, and therefore detailed structural analyses and studies of inhibitor interactions are very important research objectives. Spin labeling of the V-ATPase holoenzyme from the tobacco hornworm Manduca sexta and V-ATPase in isolated yeast (Saccharomyces cerevisiae) vacuoles was accomplished by two novel methods involving the covalent binding of a (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) derivative of N,N-dicyclohexylcarbodiimide (DCC) to the essential glutamate residue in the active site and the noncovalent interaction of a radical analogue of the highly potent inhibitor archazolid, a natural product from myxobacteria. Both complexes were evaluated in detail by electron paramagnetic resonance (EPR) spectroscopic studies and double electron-electron resonance (DEER) measurements, revealing insight into the inhibitor binding mode, dynamics, and stoichiometry as well as into the structure of the central functional subunitc of these medicinally important hetero-multimeric proton-translocating proteins. This study also demonstrates the usefulness of natural product derived spin labels as tools in medicinal chemistry.
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [SFB 813, SFB 431, SFB 944, Schwerpunktprogramm SPP1601, Forschergruppe 1406]; Generous financial support by the Deutsche Forschungsgemeinschaft (DFG) (SFB 813, SFB 431, SFB 944, Schwerpunktprogramm SPP1601 and Forschergruppe 1406) is most gratefully acknowledged. We thank Andreas J. Schneider (University of Bonn) for excellent HPLC support, Dr. Frank Rominger (University of Heidelberg) for X-ray structure analysis, and Wiebke Ahlbrecht for early exploratory studies.
dc.language.isoen
dc.publisherWILEY-V C H VERLAG GMBH
dc.relation.ispartofCHEMMEDCHEM
dc.subjectARCHANGIUM-GEPHYRA
dc.subjectarchazolid
dc.subjectBIOLOGICAL EVALUATION
dc.subjectBREAST-CANCER
dc.subjectChemistry, Medicinal
dc.subjectEPR spectroscopy
dc.subjectHIGHLY POTENT
dc.subjectHUMAN PANCREATIC-CANCER
dc.subjectMEDIATED CROSS-LINKING
dc.subjectMYXOBACTERIUM CYSTOBACTER-VIOLACEUS
dc.subjectnatural products
dc.subjectPharmacology & Pharmacy
dc.subjectPLASMA-MEMBRANE
dc.subjectspin labels
dc.subjectSTRUCTURAL ELUCIDATION
dc.subjectV-ATPase
dc.subjectVACUOLAR H+-ATPASE
dc.titleEPR Studies of V-ATPase with Spin-Labeled Inhibitors DCC and Archazolid: Interaction Dynamics with Proton Translocating Subunit c
dc.typejournal article
dc.identifier.doi10.1002/cmdc.201500500
dc.identifier.isiISI:000370738300008
dc.description.volume11
dc.description.issue4
dc.description.startpage420
dc.description.endpage428
dc.contributor.orcid0000-0002-5888-0157
dc.contributor.orcid0000-0002-5761-5968
dc.contributor.orcid0000-0001-6131-313X
dc.contributor.orcid0000-0003-0023-3413
dc.contributor.researcheridH-3791-2014
dc.contributor.researcheridC-1428-2009
dc.contributor.researcheridAAE-4315-2020
dc.contributor.researcheridK-9268-2015
dc.identifier.eissn18607187
dc.publisher.placePOSTFACH 101161, 69451 WEINHEIM, GERMANY
dcterms.isPartOf.abbreviationChemMedChem
crisitem.author.deptUniversität Osnabrück-
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptFB 04 - Physik-
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptUniversität Osnabrück-
crisitem.author.deptUniversität Osnabrück-
crisitem.author.deptidfb05-
crisitem.author.deptidfb04-
crisitem.author.deptidfb05-
crisitem.author.orcid0000-0003-0023-3413-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidGoHa001-
crisitem.author.netidBoSv426-
crisitem.author.netidStHe633-
crisitem.author.netidWiHe990-
crisitem.author.netidHuMa001-
crisitem.author.netidMeDi001-
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