TY  - JOUR
A1  - Müller, Diana
A1  - Bessi, Irene
A1  - Richter, Christian
A1  - Schwalbe, Harald
T1  - The Folding Landscapes of Human Telomeric RNA and DNA G‐Quadruplexes are Markedly Different
JF  - Angewandte Chemie International Edition
N2  - We investigated the folding kinetics of G‐quadruplex (G4) structures by comparing the K\(^{+}\)‐induced folding of an RNA G4 derived from the human telomeric repeat‐containing RNA (TERRA25) with a sequence homologous DNA G4 (wtTel25) using CD spectroscopy and real‐time NMR spectroscopy. While DNA G4 folding is biphasic, reveals kinetic partitioning and involves kinetically favoured off‐pathway intermediates, RNA G4 folding is faster and monophasic. The differences in kinetics are correlated to the differences in the folded conformations of RNA vs. DNA G4s, in particular with regard to the conformation around the glycosidic torsion angle χ that uniformly adopts anti conformations for RNA G4s and both, syn and anti conformation for DNA G4s. Modified DNA G4s with \(^{19}\)F bound to C2′ in arabino configuration adopt exclusively anti conformations for χ. These fluoro‐modified DNA (antiTel25) reveal faster folding kinetics and monomorphic conformations similar to RNA G4s, suggesting the correlation between folding kinetics and pathways with differences in χ angle preferences in DNA and RNA, respectively.
KW  - folding landscapes
KW  - G-quadruplexes
KW  - kinetics
KW  - real-time NMR spectroscopy
KW  - TERRA RNA
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238917
VL  - 60
IS  - 19
SP  - 10895
EP  - 10901
ER  - 
TY  - JOUR
A1  - Rajab, Suhaila
A1  - Bismin, Leah
A1  - Schwarze, Simone
A1  - Pinggera, Alexandra
A1  - Greger, Ingo H.
A1  - Neuweiler, Hannes
T1  - Allosteric coupling of sub-millisecond clamshell motions in ionotropic glutamate receptor ligand-binding domains
JF  - Communications Biology
N2  - Ionotropic glutamate receptors (iGluRs) mediate signal transmission in the brain and are important drug targets. Structural studies show snapshots of iGluRs, which provide a mechanistic understanding of gating, yet the rapid motions driving the receptor machinery are largely elusive. Here we detect kinetics of conformational change of isolated clamshell-shaped ligand-binding domains (LBDs) from the three major iGluR sub-types, which initiate gating upon binding of agonists. We design fluorescence probes to measure domain motions through nanosecond fluorescence correlation spectroscopy. We observe a broad kinetic spectrum of LBD dynamics that underlie activation of iGluRs. Microsecond clamshell motions slow upon dimerization and freeze upon binding of full and partial agonists. We uncover allosteric coupling within NMDA LBD hetero-dimers, where binding of L-glutamate to the GluN2A LBD stalls clamshell motions of the glycine-binding GluN1 LBD. Our results reveal rapid LBD dynamics across iGluRs and suggest a mechanism of negative allosteric cooperativity in NMDA receptors.
KW  - fluorescence spectroscopy
KW  - kinetics
KW  - ligand-gated ion channels
KW  - molecular neuroscience
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261678
VL  - 4
IS  - 1
ER  - 
TY  - JOUR
A1  - Scheiner, Matthias
A1  - Sink, Alexandra
A1  - Spatz, Philipp
A1  - Endres, Erik
A1  - Decker, Michael
T1  - Photopharmacology on Acetylcholinesterase: Novel Photoswitchable Inhibitors with Improved Pharmacological Profiles
JF  - ChemPhotoChem
N2  - Considerable effort has previously been invested in a light‐controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene‐based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo‐controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light‐controlled tacrine‐based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis‐enriched form showed an 8.4‐fold higher inhibition of hAChE compared with its trans‐enriched form and was about 30‐fold more active than the reference compound tacrine with a single‐digit nanomolar inhibition. We went beyond proof‐of‐concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, “cis‐on” effect, and pronounces differences between the photoisomers.
KW  - azobenzenes
KW  - enzymes
KW  - kinetics
KW  - photopharmacology
KW  - tacrine
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218445
VL  - 5
IS  - 2
SP  - 149
EP  - 159
ER  -