A pharmacological master key mechanism that unlocks the selectivity filter gate in K + channels-Reference-Cited by-同舟云学术

A pharmacological master key mechanism that unlocks the selectivity filter gate in K + channels

Published:2019-02-22 Issue:6429 Volume:363 Page:875-880
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Schewe Marcus¹^ORCID,Sun Han²^ORCID,Mert Ümit¹,Mackenzie Alexandra³⁴⁵,Pike Ashley C. W.³^ORCID,Schulz Friederike¹^ORCID,Constantin Cristina⁶⁷^ORCID,Vowinkel Kirsty S.⁸^ORCID,Conrad Linus J.⁴⁵^ORCID,Kiper Aytug K.⁸^ORCID,Gonzalez Wendy⁹¹⁰^ORCID,Musinszki Marianne¹^ORCID,Tegtmeier Marie¹,Pryde David C.¹¹^ORCID,Belabed Hassane¹²,Nazare Marc¹²^ORCID,de Groot Bert L.¹³^ORCID,Decher Niels⁸^ORCID,Fakler Bernd⁶⁷,Carpenter Elisabeth P.³⁴^ORCID,Tucker Stephen J.⁴⁵^ORCID,Baukrowitz Thomas¹

Affiliation:

1. Institute of Physiology, Christian-Albrechts University of Kiel, 24118 Kiel, Germany.

2. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department of Structural Biology, 13125 Berlin, Germany.

3. Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.

4. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK.

5. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.

6. Institute of Physiology II, Albert-Ludwigs University of Freiburg, 79104 Freiburg, Germany.

7. Centers for Biological Signaling Studies CIBSS and BIOSS, 79104 Freiburg, Germany.

8. Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, Germany.

9. Centro de Bioinformatica y Simulacion Molecular, Universidad de Talca, 3465548 Talca, Chile.

10. Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3465548 Talca, Chile.

11. Pfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridgeshire CB21 6GS, UK.

12. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department of Medicinal Chemistry, 13125 Berlin, Germany.

13. Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

Abstract

A key to potassium channel activation Using drugs to activate potassium channels has the potential to treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with a defined pharmacore that use a similar mechanism to activate many types of potassium channels. X-ray crystallography, functional analysis, and molecular dynamics simulations showed that the NCAs bind below the selectivity filter to open the filter gate and activate the channels. Targeting this NCA site might be exploited in rational drug design. Science , this issue p. 875

Funder

Wellcome Trust

Engineering and Physical Sciences Research Council

Biotechnology and Biological Sciences Research Council

Deutsche Forschungsgemeinschaft

Innovative Medicines Initiative Joint Undertaking

Structural Genomics Consortium

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference67 articles.