Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the det...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/57096 |
| _version_ | 1811199741094002688 |
|---|---|
| author | Demeng Sun Sanling Liu Siyu Li Mengge Zhang Fan Yang Ming Wen Pan Shi Tao Wang Man Pan Shenghai Chang Xing Zhang Longhua Zhang Changlin Tian Lei Liu |
| author_facet | Demeng Sun Sanling Liu Siyu Li Mengge Zhang Fan Yang Ming Wen Pan Shi Tao Wang Man Pan Shenghai Chang Xing Zhang Longhua Zhang Changlin Tian Lei Liu |
| author_sort | Demeng Sun |
| collection | DOAJ |
| description | Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the detailed mechanism by which Mamba1 inhibits ASIC1s, especially how Mamba1 binding to the extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 preferentially binds hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism. |
| first_indexed | 2024-04-12T01:52:24Z |
| format | Article |
| id | doaj.art-2800ac3a272d42a5ad5196853cf4e158 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:52:24Z |
| publishDate | 2020-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2800ac3a272d42a5ad5196853cf4e1582022-12-22T03:52:53ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.57096Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1Demeng Sun0Sanling Liu1Siyu Li2Mengge Zhang3Fan Yang4Ming Wen5Pan Shi6Tao Wang7Man Pan8Shenghai Chang9Xing Zhang10Longhua Zhang11Changlin Tian12https://orcid.org/0000-0001-9315-900XLei Liu13Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China; Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHigh Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, ChinaTsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, ChinaSchool of Medicine, Zhejiang University, Hangzhou, ChinaSchool of Medicine, Zhejiang University, Hangzhou, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, ChinaHefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, ChinaTsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, ChinaAcid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the detailed mechanism by which Mamba1 inhibits ASIC1s, especially how Mamba1 binding to the extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 preferentially binds hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.https://elifesciences.org/articles/57096acid-sensing ion channelsnake toxincryo-EM structureinhibition |
| spellingShingle | Demeng Sun Sanling Liu Siyu Li Mengge Zhang Fan Yang Ming Wen Pan Shi Tao Wang Man Pan Shenghai Chang Xing Zhang Longhua Zhang Changlin Tian Lei Liu Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 eLife acid-sensing ion channel snake toxin cryo-EM structure inhibition |
| title | Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| title_full | Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| title_fullStr | Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| title_full_unstemmed | Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| title_short | Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| title_sort | structural insights into human acid sensing ion channel 1a inhibition by snake toxin mambalgin1 |
| topic | acid-sensing ion channel snake toxin cryo-EM structure inhibition |
| url | https://elifesciences.org/articles/57096 |
| work_keys_str_mv | AT demengsun structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT sanlingliu structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT siyuli structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT menggezhang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT fanyang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT mingwen structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT panshi structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT taowang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT manpan structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT shenghaichang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT xingzhang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT longhuazhang structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT changlintian structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 AT leiliu structuralinsightsintohumanacidsensingionchannel1ainhibitionbysnaketoxinmambalgin1 |