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Structure of Lymphocyte Potassium Channel K v1.3 and Modulation by Cell-Penetrating Immunomodulatory Plant Defensin

94 Pages Posted: 10 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Seow Theng Ong

Seow Theng Ong

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Sanling Liu

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

Saumya Bajaj

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Yue Zhao

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

Mark R. Tanner

Baylor College of Medicine - Department of Molecular Physiology and Biophysics

Shih Chieh Chang

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Yong Zhang

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

Bankala Krishnarjuna

Monash University - Medicinal Chemistry

Xuan Rui Ng

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Rodrigo A. V. Morales

Monash University - Medicinal Chemistry

Wei Chen Ming

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Dahai Luo

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Dharmeshkumar Patel

The University of Sydney - School of Physics

Sabina Yasmin

The University of Sydney - School of Physics

Jeremy Jun Heng Ng

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Hai M. Nguyen

University of California, Davis - Department of Pharmacology

El Sahili Abbas

Nanyang Technological University (NTU) - Structural Biology and Biochemistry

Julien Lescar

Nanyang Technological University (NTU) - Structural Biology and Biochemistry

Rahul Patil

Monash University - Centre for Drug Candidate Optimisation

Susan A. Charman

Monash University - Centre for Drug Candidate Optimisation

Edward Robins

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Julian Goggi

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Wen Tan Peng

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Pragalath Sadasivam

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Boominathan Ramasamy

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Hartimath SV

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Vikas Dhawan

Peptides International, Inc.

Janna Bednenko

TetraGenetics Inc.

Paul Colussi

TetraGenetics Inc.

Heike Wulff

University of California, Davis - Department of Pharmacology

Longhua Zhang

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

Michael Pennington

Peptides International, Inc.

Serdar Kuyucak

The University of Sydney - School of Physics

Raymond S. Norton

Monash University - Medicinal Chemistry

Christine Beeton

Baylor College of Medicine - Department of Molecular Physiology and Biophysics

Changlin Tian

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

George Chandy

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

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Abstract

Here, we report the cryo-electron microscopy structure of the human voltage-gated hKv1.3 potassium channel in T lymphocytes in complex with its accessory protein Kvβ2 at 3.4Å resolution. We also describe EgK5, a designed peptide-analogue of plant defensins from grapevine and oil palm, that modulates hKv1.3/Kvβ2 by a distinctive mechanism. EgK5 enters cells and binds to the channel near its inner pore and also to Kvβ2. This interaction elevates flexibility and induces conformational changes in the hKv1.3/Kvβ2 complex, resulting in the suppression of hKv1.3 currents. EgK5 inhibits the proliferation of effector memory T cells, a subset enriched amongst pathogenic autoreactive T cells in autoimmune diseases, and treats disease in rat models of rheumatoid arthritis and atopic dermatitis with no signs of toxicity at 10-100 times the in vivo dose. We provide a framework for the structure-guided discovery of drugs that modulate channel activity by intracellular binding and conductance-reduction.

Keywords: Kv1.3, Kv beta-2, potassium channel, Cryo-electron microscopy, plant defensin, cell-penetrating peptide, peptide therapeutic, effector memory T cell, rheumatoid arthritis, atopic dermatitis, autoimmune disease, grapevine, oil palm

Suggested Citation

Ong, Seow Theng and Liu, Sanling and Bajaj, Saumya and Zhao, Yue and Tanner, Mark R. and Chang, Shih Chieh and Zhang, Yong and Krishnarjuna, Bankala and Ng, Xuan Rui and Morales, Rodrigo A. V. and Ming, Wei Chen and Luo, Dahai and Patel, Dharmeshkumar and Yasmin, Sabina and Ng, Jeremy Jun Heng and Nguyen, Hai M. and Abbas, El Sahili and Lescar, Julien and Patil, Rahul and Charman, Susan A. and Robins, Edward and Goggi, Julian and Peng, Wen Tan and Sadasivam, Pragalath and Ramasamy, Boominathan and SV, Hartimath and Dhawan, Vikas and Bednenko, Janna and Colussi, Paul and Wulff, Heike and Zhang, Longhua and Pennington, Michael and Kuyucak, Serdar and Norton, Raymond S. and Beeton, Christine and Tian, Changlin and Chandy, George, Structure of Lymphocyte Potassium Channel K v1.3 and Modulation by Cell-Penetrating Immunomodulatory Plant Defensin (October 10, 2019). CELL-D-19-02594. Available at SSRN: https://ssrn.com/abstract=3467250 or http://dx.doi.org/10.2139/ssrn.3467250
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Seow Theng Ong

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Singapore

Sanling Liu

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale ( email )

96, Jinzhai Road
Hefei, Anhui 230026
China

Saumya Bajaj

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Singapore

Yue Zhao

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

hefei, anhui
China

Mark R. Tanner

Baylor College of Medicine - Department of Molecular Physiology and Biophysics

One Baylor Plaza - BCM335
Houston, TX 77030
United States

Shih Chieh Chang

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

Yong Zhang

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale

96, Jinzhai Road
Hefei, Anhui 230026
China

Bankala Krishnarjuna

Monash University - Medicinal Chemistry ( email )

Australia

Xuan Rui Ng

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

Rodrigo A. V. Morales

Monash University - Medicinal Chemistry

Australia

Wei Chen Ming

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

Dahai Luo

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

Dharmeshkumar Patel

The University of Sydney - School of Physics

Sydney, New South Wales 2006
Australia

Sabina Yasmin

The University of Sydney - School of Physics

Sydney, New South Wales 2006
Australia

Jeremy Jun Heng Ng

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Singapore

Hai M. Nguyen

University of California, Davis - Department of Pharmacology

One Shields Avenue
Davis, CA 95616
United States

El Sahili Abbas

Nanyang Technological University (NTU) - Structural Biology and Biochemistry ( email )

Singapore

Julien Lescar

Nanyang Technological University (NTU) - Structural Biology and Biochemistry ( email )

Singapore

Rahul Patil

Monash University - Centre for Drug Candidate Optimisation

Australia

Susan A. Charman

Monash University - Centre for Drug Candidate Optimisation

Australia

Edward Robins

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium ( email )

Singapore

Julian Goggi

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium ( email )

Singapore

Wen Tan Peng

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium ( email )

Singapore

Pragalath Sadasivam

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium ( email )

Singapore

Boominathan Ramasamy

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium ( email )

Singapore

Hartimath SV

Agency for Science, Technology and Research (A*STAR) - Singapore Bioimaging Consortium

Singapore

Vikas Dhawan

Peptides International, Inc. ( email )

United States

Janna Bednenko

TetraGenetics Inc. ( email )

United States

Paul Colussi

TetraGenetics Inc. ( email )

United States

Heike Wulff

University of California, Davis - Department of Pharmacology ( email )

One Shields Avenue
Davis, CA 95616
United States

Longhua Zhang

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale ( email )

96, Jinzhai Road
Hefei, Anhui 230026
China

Michael Pennington

Peptides International, Inc. ( email )

United States

Serdar Kuyucak

The University of Sydney - School of Physics

New South Wales, 2006
Australia

Raymond S. Norton

Monash University - Medicinal Chemistry

Australia

Christine Beeton

Baylor College of Medicine - Department of Molecular Physiology and Biophysics ( email )

One Baylor Plaza - BCM335
Houston, TX 77030
United States

Changlin Tian

University of Science and Technology of China (USTC) - Hefei National Laboratory for Physical Sciences at the Microscale ( email )

96, Jinzhai Road
Hefei, Anhui 230026
China

George Chandy (Contact Author)

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

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