11,853 research outputs found
Recommended from our members
Kaye Bock Award Winners
No full textThe Kaye Bock Award is given to the author (or authors) of the best paper, as determined by the editors, in each issue of the Berkeley Planning Journal that was written by a student (or a team of students). The award is named in loving memory of Kaye Bock to honor her unbounded concern for and commitment to graduate students. This award is also intended to be an eternal expression of gratitude from the Berkeley Planning Journal to Kaye for her critical and caring support during our first two decades of publication. The Kaye Bock Award is accompanied by a $250 cash gift
Dynamic ligand binding of dualsteric (allosteric/orthosteric) molecular probes controls the graded activation of muscarinic acetylcholine receptors
No full textWe investigated a class of bitopic (dualsteric) ligands of the M2 acetylcholine muscarinic receptor (M2AChR), i.e. compounds whose pharmacophoric groups are able to target the orthosteric as well as the allosteric binding site of the receptor.1,2 These model derivatives are composed of an allosteric fragment, an intermediate linker and an orthosteric moiety. As an example, ligands 1 and 2 incorporate the molecular portion of the allosteric compound Naphmethonium and the potent muscarinic agonist Iperoxo, which are connected by a flexible or a rigidified spacer group, respectively (Figure 1). These bipharmacophoric molecular probes were found to switch between two different binding orientations, resulting in both active and inactive populations of receptors bound by a given ligand, a behavior that has been termed dynamic ligand binding.3
Figure 1
In this study, pharmacological data analysis and computational simulations based on active and inactive M2AChR crystal structures led to identify two distinct binding topographies in a group of dualsteric partial agonists. One binding mode, which resembled that of the co-crystallized orthosteric ligand Iperoxo, engendered an agonist response. Conversely, dualsteric ligands binding to the allosteric site only showed a receptor-complex comparable to that of allosteric modulators. Thus, the observed agonist efficacies depended on the fraction of dualsteric (i.e. active) vs. purely allosteric (i.e. inactive) binding modes.4
References
1. Antony, J.; Kellershon, K.; Mohr-Andrä, M.; Kebig, A.; Prilla, S.; Muth, M.; Heller, E.; Disingrini, T.; Dallanoce, C.; Bertoni, S.; Schrobang, J.; Tränkle, C.; Kostenis, E.; Christopoulos, A.; Höltje, H.-D.; Barocelli, E.; De Amici, M.; Holzgrabe, U.; Mohr, K. FASEB J. 2009, 23, 442-450.
2. Bock, A.; Merten, N.; Schrage, R.; Dallanoce, C.; Bätz, J.; Klöckner, J.; Schmitz, J.; Matera, C.; Simon, K.; Kebig, A.; Peters, L.; Müller, A.; Schrobang-Ley, J.; Tränkle, C.; Hoffmann, C.; De Amici, M.; Holzgrabe, U.; Kostenis, E.; Mohr; K. Nat. Commun. 2012, 3:1044, doi: 10.1038/ncomms2028.
3. Bock, A.; Chirinda, B.; Krebs, F.; Messerer, R.; Bätz, J.; Muth, M.; Dallanoce, C.; Klingenthal, D.; Tränkle, C.; Hoffmann, C.; De Amici, M.; Holzgrabe, U.; Kostenis, E.; Mohr, K. Nat. Chem. Biol. 2014, 10, 18-20.
4. Bock, A.; Bermudez, M.; Krebs, F.; Matera, C.; Chirinda, B.; Sydow, D.; Dallanoce, C.; Holzgrabe, H.; De Amici, M.; Lohse, M.; Wolber, G.; Mohr, K. J. Biol. Chem., in press
Molecular rigidity in dualsteric agonists affects signaling bias of the muscarinic M2 acetylcholine receptor
No full textFor the human M2 muscarinic receptor the crystal structures in the active [1] and the inactive [2] conformation are available. Both structures suggest a low tolerance of the receptor protein towards spatial restriction between the allosteric and the orthosteric binding site.
Dualsteric compounds consist of covalently linked moieties that address the orthosteric and the allosteric binding site, respectively. Thus, it is possible to constrain receptor flexibility.
In a previous study, it was found that dualsteric compounds such as iper-6-naph, in which the orthosteric and allosteric moiety are linked via a hexamethylene chain, show biased signaling (i.e. a preference for Gi over Gs signaling) [3].
Here we present new dualsteric ligands, which due to their molecular properties should further restrict conformational transitions of the receptor. Surprisingly, signaling bias was abolished. These unexpected findings will be discussed in our poster.
[1] Haga K. et al.: Nature 2012
[2] Kruse A. et al.: Nature 2013
[3] Bock A. et al.: Nat Chem Biol. 201
Recommended from our members
Kaye Bock Student Paper Award
No full textThe Kaye Bock Student Paper Award is given to the author of the paper that is both an outstanding example of scholarship and exemplifies Kaye's commitment to underrepresented issues or peoples. The award is named in loving memory of Kaye Bock to honor her unbounded concern for and commitment to graduate students in the Department of City and Regional Planning. It is also intended as an expression of gratitude from the Berkeley Planning Journal to Kaye for her critical and caring support of the journal during our first two decades of publication. The winner is chosen by the editors of each volume of the Berkeley Planning Journal. The Kaye Bock Student Paper Award is accompanied by a $250 cash gift
Krimp met de K van kansen
No full textEssay. Vergrijzing, vertrekkende mensen, minder voorzieningen: aan duidelijkheid laat de problematiek van krimpregio’s weinig te wensen over. Maar het ‘Randland’ biedt ook kansen, juist in deze tijden van woon-, klimaat- en pandemie-uitdagingen. Het is tijd dat Rijk en regio een gezamenlijke sprong voorwaarts maken, aldus ‘krimpprofessor’ Bettina Bock
Zum Unterschied von Prüfungs- und Studienleistungen
No full textBock K-D. Zum Unterschied von Prüfungs- und Studienleistungen. Das Hochschulwesen HSW. 2000;48(1):15-23
Klasse in Masse, jetzt Studiengebühren zu fordern ist absurd
No full textBock K-D. Klasse in Masse, jetzt Studiengebühren zu fordern ist absurd. Die Tageszeitung TAZ. 16. August 2004
Long-lived metastable state and hysteresis in the binding of acetylcholine to Torpedo californica acetylcholine receptor
No full textChang HW, Bock E, Neumann E. Long-lived metastable state and hysteresis in the binding of acetylcholine to Torpedo californica acetylcholine receptor. Biochemistry. 1984;23(20):4546-4556
Altersruhegelder im Niveauvergleich - eine methodenkritische Durchsicht der "empirischen" Argumente für und wider eine Rentenbesteuerung
No full textBock K-D. Altersruhegelder im Niveauvergleich - eine methodenkritische Durchsicht der "empirischen" Argumente für und wider eine Rentenbesteuerung. Deutsche Rentenversicherung DRV. 2000;2000(12):758-785
Strukturgeschichte der Assistentur. Personalgefüge, Wert- u. Zielvorstellungen in d. dt. Univ. d. 19. u. 20. Jahrhunderts
No full textBock K-D. Strukturgeschichte der Assistentur. Personalgefüge, Wert- u. Zielvorstellungen in d. dt. Univ. d. 19. u. 20. Jahrhunderts. Wissenschaftstheorie, Wissenschaftspolitik, Wissenschaftsplanung. Vol 29. Düsseldorf: Bertelsmann Universitätsverlag; 1972
- …
