Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug-Reference-Cited by-同舟云学术

Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug

Published:2022-01-28 Issue:5 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Tyagi Anu¹^ORCID,Ahmed Tofayel²,Jian Shi³,Bajaj Saumya¹⁴,Ong Seow Theng⁴^ORCID,Goay Stephanie Shee Min⁴,Zhao Yue⁵,Vorobyov Igor⁶⁷^ORCID,Tian Changlin⁵,Chandy K. George⁴^ORCID,Bhushan Shashi¹⁸

Affiliation:

1. School of Biological Sciences, Nanyang Technological University, Singapore 637551

2. Department of Structural Biology, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany

3. Department of Biological Sciences, National University of Singapore, Singapore 117557

4. LKCMedicine-ICESing Ion Channel Platform, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 636921

5. Hefei National Laboratory of Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China

6. Department of Physiology and Membrane Biology, University of California, Davis, CA 95616

7. Department of Pharmacology, University of California, Davis, CA 95616

8. Nanyang Institute of Structural Biology, Nanyang Technological University, Singapore 639798

Abstract

Significance Voltage-gated potassium channels (Kv) open with membrane depolarization and allow the flow of K + ions. Ion flow is tightly governed by time-dependent entry into nonconducting inactivated states. Here, we focus on Kv1.3, a channel of physiological importance in immune cells. We used cryogenic electron microscopy to determine structures of human Kv1.3 alone and bound to dalazatide, a peptide inhibitor in human trials. In the unbound state, Kv1.3’s outer pore is rearranged compared to all other K + channels analyzed. Interaction of dalazatide with Kv1.3’s outer pore causes a dynamic rearrangement of the selectivity filter as Kv1.3 enters a drug-blocked state.

Funder

Ministry of Education - Singapore

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2113536119

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