Structure of the human voltage-gated sodium channel Na v 1.4 in complex with β1
Voltage-gated sodium (Na ) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na channel has hampered mechanistic understanding. Here, we report the cryo-electron m...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2018-10, Vol.362 (6412) |
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| creator | Pan, Xiaojing Li, Zhangqiang Zhou, Qiang Shen, Huaizong Wu, Kun Huang, Xiaoshuang Chen, Jiaofeng Zhang, Juanrong Zhu, Xuechen Lei, Jianlin Xiong, Wei Gong, Haipeng Xiao, Bailong Yan, Nieng |
| description | Voltage-gated sodium (Na
) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na
channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na
1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na
permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na
channels. The structure provides a path toward mechanistic investigation of Na
channels and drug discovery for Na
channelopathies. |
| doi_str_mv | 10.1126/science.aau2486 |
| format | Article |
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) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na
channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na
1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na
permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na
channels. The structure provides a path toward mechanistic investigation of Na
channels and drug discovery for Na
channelopathies.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aau2486</identifier><identifier>PMID: 30190309</identifier><language>eng</language><publisher>United States</publisher><subject>Allosteric Regulation ; Amino Acid Sequence ; Channelopathies - genetics ; Channelopathies - metabolism ; Cryoelectron Microscopy ; Drug Discovery ; HEK293 Cells ; Humans ; Mutation ; NAV1.4 Voltage-Gated Sodium Channel - chemistry ; NAV1.4 Voltage-Gated Sodium Channel - genetics ; NAV1.4 Voltage-Gated Sodium Channel - ultrastructure ; Protein Domains ; Voltage-Gated Sodium Channel beta-4 Subunit - chemistry ; Voltage-Gated Sodium Channel beta-4 Subunit - genetics ; Voltage-Gated Sodium Channel beta-4 Subunit - ultrastructure</subject><ispartof>Science (American Association for the Advancement of Science), 2018-10, Vol.362 (6412)</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1506-2004f29bbb5e9b2daaaa159370e20e2c51703aeb5450727f0dc53f763f271af43</citedby><cites>FETCH-LOGICAL-c1506-2004f29bbb5e9b2daaaa159370e20e2c51703aeb5450727f0dc53f763f271af43</cites><orcidid>0000-0003-1882-5361 ; 0000-0002-9384-8742 ; 0000-0002-3075-8272 ; 0000-0001-5003-8531 ; 0000-0002-6237-8813 ; 0000-0002-5532-1640 ; 0000-0003-4829-7416 ; 0000-0002-3296-2293 ; 0000-0002-1216-5393</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30190309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pan, Xiaojing</creatorcontrib><creatorcontrib>Li, Zhangqiang</creatorcontrib><creatorcontrib>Zhou, Qiang</creatorcontrib><creatorcontrib>Shen, Huaizong</creatorcontrib><creatorcontrib>Wu, Kun</creatorcontrib><creatorcontrib>Huang, Xiaoshuang</creatorcontrib><creatorcontrib>Chen, Jiaofeng</creatorcontrib><creatorcontrib>Zhang, Juanrong</creatorcontrib><creatorcontrib>Zhu, Xuechen</creatorcontrib><creatorcontrib>Lei, Jianlin</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Gong, Haipeng</creatorcontrib><creatorcontrib>Xiao, Bailong</creatorcontrib><creatorcontrib>Yan, Nieng</creatorcontrib><title>Structure of the human voltage-gated sodium channel Na v 1.4 in complex with β1</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Voltage-gated sodium (Na
) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na
channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na
1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na
permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na
channels. The structure provides a path toward mechanistic investigation of Na
channels and drug discovery for Na
channelopathies.</description><subject>Allosteric Regulation</subject><subject>Amino Acid Sequence</subject><subject>Channelopathies - genetics</subject><subject>Channelopathies - metabolism</subject><subject>Cryoelectron Microscopy</subject><subject>Drug Discovery</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mutation</subject><subject>NAV1.4 Voltage-Gated Sodium Channel - chemistry</subject><subject>NAV1.4 Voltage-Gated Sodium Channel - genetics</subject><subject>NAV1.4 Voltage-Gated Sodium Channel - ultrastructure</subject><subject>Protein Domains</subject><subject>Voltage-Gated Sodium Channel beta-4 Subunit - chemistry</subject><subject>Voltage-Gated Sodium Channel beta-4 Subunit - genetics</subject><subject>Voltage-Gated Sodium Channel beta-4 Subunit - ultrastructure</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRS0EoqWwZofmB9KO7Tiul6jiJVWABKwjxxk3QXlUccLjt_gQvomgFkZXmsW9dzQ6jJ1znHMukkVwJTWO5tYOIl4mB2zK0ajICJSHbIook2iJWk3YSQiviKNn5DGbSOQGJZope3zqu8H1Q0fQeugLgmKobQNvbdXbDUUb21MOoc3LoQZX2KahCu4tvAGfx1A24Np6W9EHvJd9Ad9f_JQdeVsFOtvvGXu5vnpe3Ubrh5u71eU6clxhEgnE2AuTZZkik4ncjsPH5zSSGOUU1ygtZSpWqIX2mDslvU6kF5pbH8sZW-zuuq4NoSOfbruytt1nyjH9ZZPu2aR7NmPjYtfYDllN-X_-D4b8Ae4WYbw</recordid><startdate>20181019</startdate><enddate>20181019</enddate><creator>Pan, Xiaojing</creator><creator>Li, Zhangqiang</creator><creator>Zhou, Qiang</creator><creator>Shen, Huaizong</creator><creator>Wu, Kun</creator><creator>Huang, Xiaoshuang</creator><creator>Chen, Jiaofeng</creator><creator>Zhang, Juanrong</creator><creator>Zhu, Xuechen</creator><creator>Lei, Jianlin</creator><creator>Xiong, Wei</creator><creator>Gong, Haipeng</creator><creator>Xiao, Bailong</creator><creator>Yan, Nieng</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0003-1882-5361</orcidid><orcidid>https://orcid.org/0000-0002-9384-8742</orcidid><orcidid>https://orcid.org/0000-0002-3075-8272</orcidid><orcidid>https://orcid.org/0000-0001-5003-8531</orcidid><orcidid>https://orcid.org/0000-0002-6237-8813</orcidid><orcidid>https://orcid.org/0000-0002-5532-1640</orcidid><orcidid>https://orcid.org/0000-0003-4829-7416</orcidid><orcidid>https://orcid.org/0000-0002-3296-2293</orcidid><orcidid>https://orcid.org/0000-0002-1216-5393</orcidid></search><sort><creationdate>20181019</creationdate><title>Structure of the human voltage-gated sodium channel Na v 1.4 in complex with β1</title><author>Pan, Xiaojing ; Li, Zhangqiang ; Zhou, Qiang ; Shen, Huaizong ; Wu, Kun ; Huang, Xiaoshuang ; Chen, Jiaofeng ; Zhang, Juanrong ; Zhu, Xuechen ; Lei, Jianlin ; Xiong, Wei ; Gong, Haipeng ; Xiao, Bailong ; Yan, Nieng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1506-2004f29bbb5e9b2daaaa159370e20e2c51703aeb5450727f0dc53f763f271af43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Allosteric Regulation</topic><topic>Amino Acid Sequence</topic><topic>Channelopathies - genetics</topic><topic>Channelopathies - metabolism</topic><topic>Cryoelectron Microscopy</topic><topic>Drug Discovery</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mutation</topic><topic>NAV1.4 Voltage-Gated Sodium Channel - chemistry</topic><topic>NAV1.4 Voltage-Gated Sodium Channel - genetics</topic><topic>NAV1.4 Voltage-Gated Sodium Channel - ultrastructure</topic><topic>Protein Domains</topic><topic>Voltage-Gated Sodium Channel beta-4 Subunit - chemistry</topic><topic>Voltage-Gated Sodium Channel beta-4 Subunit - genetics</topic><topic>Voltage-Gated Sodium Channel beta-4 Subunit - ultrastructure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pan, Xiaojing</creatorcontrib><creatorcontrib>Li, Zhangqiang</creatorcontrib><creatorcontrib>Zhou, Qiang</creatorcontrib><creatorcontrib>Shen, Huaizong</creatorcontrib><creatorcontrib>Wu, Kun</creatorcontrib><creatorcontrib>Huang, Xiaoshuang</creatorcontrib><creatorcontrib>Chen, Jiaofeng</creatorcontrib><creatorcontrib>Zhang, Juanrong</creatorcontrib><creatorcontrib>Zhu, Xuechen</creatorcontrib><creatorcontrib>Lei, Jianlin</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Gong, Haipeng</creatorcontrib><creatorcontrib>Xiao, Bailong</creatorcontrib><creatorcontrib>Yan, Nieng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pan, Xiaojing</au><au>Li, Zhangqiang</au><au>Zhou, Qiang</au><au>Shen, Huaizong</au><au>Wu, Kun</au><au>Huang, Xiaoshuang</au><au>Chen, Jiaofeng</au><au>Zhang, Juanrong</au><au>Zhu, Xuechen</au><au>Lei, Jianlin</au><au>Xiong, Wei</au><au>Gong, Haipeng</au><au>Xiao, Bailong</au><au>Yan, Nieng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of the human voltage-gated sodium channel Na v 1.4 in complex with β1</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2018-10-19</date><risdate>2018</risdate><volume>362</volume><issue>6412</issue><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Voltage-gated sodium (Na
) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na
channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na
1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na
permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na
channels. The structure provides a path toward mechanistic investigation of Na
channels and drug discovery for Na
channelopathies.</abstract><cop>United States</cop><pmid>30190309</pmid><doi>10.1126/science.aau2486</doi><orcidid>https://orcid.org/0000-0003-1882-5361</orcidid><orcidid>https://orcid.org/0000-0002-9384-8742</orcidid><orcidid>https://orcid.org/0000-0002-3075-8272</orcidid><orcidid>https://orcid.org/0000-0001-5003-8531</orcidid><orcidid>https://orcid.org/0000-0002-6237-8813</orcidid><orcidid>https://orcid.org/0000-0002-5532-1640</orcidid><orcidid>https://orcid.org/0000-0003-4829-7416</orcidid><orcidid>https://orcid.org/0000-0002-3296-2293</orcidid><orcidid>https://orcid.org/0000-0002-1216-5393</orcidid><oa>free_for_read</oa></addata></record> |
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| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Allosteric Regulation Amino Acid Sequence Channelopathies - genetics Channelopathies - metabolism Cryoelectron Microscopy Drug Discovery HEK293 Cells Humans Mutation NAV1.4 Voltage-Gated Sodium Channel - chemistry NAV1.4 Voltage-Gated Sodium Channel - genetics NAV1.4 Voltage-Gated Sodium Channel - ultrastructure Protein Domains Voltage-Gated Sodium Channel beta-4 Subunit - chemistry Voltage-Gated Sodium Channel beta-4 Subunit - genetics Voltage-Gated Sodium Channel beta-4 Subunit - ultrastructure |
| title | Structure of the human voltage-gated sodium channel Na v 1.4 in complex with β1 |
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